Arthritis Care & Research Vol. 65, No. 9, September 2013, pp 1539 –1547 DOI 10.1002/acr.22019 © 2013, American College of Rheumatology

CLINICOPATHOLOGIC CONFERENCE

A 4-Year-Old Amish Boy With Weakness, Arthritis, Rash, Verbal Delay, and Failure to Thrive REUT GURION,1 CHINASA NWANKWO,1 KABITA NANDA,2 ELIZABETH B. BROOKS,1 ANNA L. MITCHELL,1 MAX WIZNITZER,1 AND ANGELA B. ROBINSON1

CASE PRESENTATION Chief symptom A 4-year-old Amish boy presented with a 12-month history of a purplish rash on his fingers and toes.

History of the present illness: part 1 The patient was in his usual state of health until March 2010, when he developed purplish discoloration with nodules on his fingers and toes. Over the next few months, he was noted to have progressive weakness with poor appetite, fatigue, and headache. Medical care was sought for these symptoms and he was initially diagnosed with a viral illness and subsequently with streptococcal pharyngitis. He had been noted to have delayed speech development in comparison with his 7 siblings. Medical history. The patient has a history of asthma that is managed with fluticasone propionate. His family reported that he has always been small for his age. Except for verbal delays, he has otherwise been developmentally normal. Family and social history. The patient’s family history was negative for rheumatic disorders. They denied consanguinity. He has 4 cousins with Cohen syndrome. He lives on a farm with his parents and 7 older siblings. 1 Reut Gurion, DO, Chinasa Nwankwo, MD, Elizabeth B. Brooks, MD, PhD, Anna L. Mitchell, MD, Max Wiznitzer, MD, Angela B. Robinson, MD, MPH: Cleveland Case Medical Center and Rainbow Babies & Children’s Hospital, Cleveland, Ohio; 2Kabita Nanda, MD: Seattle Children’s Hospital, Seattle, Washington. Address correspondence to Reut Gurion, DO, University Hospitals Case Medical Center, Rainbow Babies & Children’s Hospital, 11100 Euclid Avenue, Cleveland, OH 44106. E-mail: [email protected]. Submitted for publication December 2, 2012; accepted in revised form March 20, 2013.

Review of systems. The family reported that he had increased sleep requirement, occasional wheeze, pain in his shins, headaches (4 –5 times in a month), and easy bruising. They denied fever, abdominal pain, nausea, vomiting, or diarrhea. Initial physical examination. Physical examination was notable for short stature (less than third percentile), shotty cervical lymphadenopathy, livedo reticularis, purplish hue over the upper eyelids, nodular vasculitic rash on his fingers and toes, hypohidrosis of the feet, and dry skin throughout. He had difficulty rising up from the floor, but did not have Gowers’ sign. He had effusions in the right wrist; the bilateral second, right fourth, and third proximal interphalangeal joints of the fingers; and both knees. Diagnostic evaluation. Recommendations were given for skin biopsy as well as complete blood count (CBC) with differential cell count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, comprehensive metabolic panel, thyroid-stimulating hormone (TSH), free thyroxine (FT4), antinuclear antibody (ANA) with extractable nuclear antigens, complement C3 and C4, urinalysis, urine protein-to-creatinine ratio, antistreptolysin O, anti–DNase B antibody, antineutrophil cytoplasmic antibody (ANCA), lysozyme, lactate dehydrogenase, uric acid, lupus anticoagulant, anticardiolipin antibodies, and cryoglobulins. Despite multiple discussions with the family, they did not comply with the recommendations for further investigation and monitoring, and chose to see a homeopathic physician.

History of the present illness: part 2 (second visit 7 months later) The patient returned to our clinic 7 months later with worsening arthritis, fatigue, weakness, and delayed growth and speech development. His mother also reported that his hair had not grown in 7 months. While reviewing his interim records, it was noted that, secondary to a fall, a head computed tomography (CT) scan had been done at an 1539

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Gurion et al ALT of 99 units/liter. Creatine phosphokinase, aldolase, CBC with differential cell count, CRP level, urinalysis, anti– double-stranded DNA antibody, cryoglobulins, lysozyme, ANCA, angiotensin-converting enzyme, and hepatitis panel were all normal or negative. Radiologic studies included normal hepatic ultrasound and normal magnetic resonance angiogram (MRA) of the neck. Magnetic resonance imaging (MRI) of the brain showed encephalomalacia of the right temporal occipital lobe with compensatory dilation of the adjacent right lateral ventricle, and abnormal signal in his subcortical and periventricular white matter (Figure 1). The MRA showed segmental areas of signal dropout at the terminus of his internal cerebral arteries bilaterally with numerous smallcaliber vessels surrounding these areas of MRA signal dropout, suggesting numerous small-caliber collateral arterial vessels (Figure 1).

SUBSEQUENT CLINICAL COURSE

Figure 1. A and B, Rash on the patient’s fingers and toes. C and D, Initial magnetic resonance imaging/magnetic resonance angiogram scan on admission demonstrates areas of right hemispheric encephalomalacia and evidence of proximal intracranial vasculopathy.

outside hospital 3 months prior to his visit that demonstrated brain calcifications and a large area of encephalomalacia in the right parietal occipital, left posterior occipital, and superior right frontal lobes. Laboratory work done at the time of the CT scan revealed alanine aminotransferase (ALT) of 137 units/liter (normal range 10 – 65), aspartate aminotransferase (AST) of 105 units/liter (normal range 10 – 60), and albumin of 3.3 gm/dl (normal range 3.4 –5.1). Physical examination. Physical examination showed decreased growth velocity of 0.6 cm in 7 months (normal for his age is 7 cm per year), hoarse voice, shotty cervical lymphadenopathy, hepatomegaly, hyperkeratosis of the feet, vasculitic rash on his fingers and toes (Figure 1), livedo reticularis, worsening arthritis, and proximal weakness. Diagnostic evaluation. He was admitted to the hospital for further diagnostic evaluation. Laboratory investigation demonstrated an ESR of 41 mm/hour (normal range 0 –13) and positive ANAs at 1:160 speckled, with positive antiRNP at 1.3 antibody index (AI; normal value ⬍1), positive anti-Ro/SSA antibody at 3.1 AI (normal value ⬍1), and positive anti–ribosomal P antibodies at 1.1 AI (normal value ⬍1). Additional testing revealed TSH of 730 mIU/ liter (normal range 0.36 –3.74), FT4 of 0.19 ng/dl (normal range 0.6 –1.5), and T3 of 49 ng/dl (normal range 100 –275). Anti–thyroid peroxidase antibodies were ⬎1,000 IU/ml (normal range 0 –34) and antithyroglobulin antibodies were ⬎3,000 IU/ml (normal range 0 – 40). The comprehensive metabolic panel showed AST of 77 units/liter and

The patient was started on low-dose levothyroxine (37.5 ␮g) with a goal of titration to achieve normal TSH. He was placed on a 3-day course of intravenous methylprednisolone (30 mg/kg) followed by 2 mg/kg/day of prednisolone. Over the next few days, he was noted to have increased fatigue and decreased activity, worsening anorexia, and minimal alopecia. He had dyspnea and required oxygen. A 20-minute electroencephalogram (EEG) showed severe diffuse encephalopathy without epileptiform discharges. A chest radiograph was normal. MRI and MRA of the chest and abdomen with gadolinium were unremarkable. Over the next 2 weeks, he had improvement of his fatigue on levothyroxine and prednisolone. He also had improvement of his thyroid function tests: TSH decreased to 230 mIU/liter and FT4 normalized to 1.03 ng/dl. While receiving corticosteroids, a skin biopsy of his left fifth toe was performed and revealed purpura with mild interface changes consistent with chilblains. He was discharged home. Approximately 15 hours after discharge, his family called and reported decreased activity, appetite, and urine output; difficulty moving his right arm; and a left facial droop. He was taken to the emergency room, where a CT scan showed acute changes of hypodensities and edema in the left caudate head, the anterior limb of the left internal capsule, and the anterior aspect of the left lentiform nucleus in addition to his encephalomalacia and ventricular dilation. He was transferred to the pediatric intensive care unit (PICU), where MRI and MRA scans were obtained and showed interval progression of occlusive vasculopathy with new infarcts of varying ages in multiple vascular distributions (Figure 2). He was started on aspirin 81 mg daily. In the PICU, a lumbar puncture was performed that was significant for 10,000 red blood cells/␮l (normal range 0 –5; reported to be a traumatic tap), 10 white blood cells/␮l (normal range 0 –10), and total protein of 165 mg/dl (normal range 15– 45 mg/dl), and a negative culture. Cerebrospinal fluid (CSF) glucose was not obtained. Further CSF

Clinicopathologic Conference

1541 tions and encephalomalacia widened the differential diagnosis to include congenital infection and central nervous system (CNS) vasculitis. During his hospitalization, his severe hypothyroidism was thought to explain most of the symptoms; however, none explained the multiple manifestations of disease under a single diagnosis. Consideration of genetic syndromes was entertained to attempt to inclusively explain his hypothyroidism, developmental delays, failure to thrive, moyamoya phenomenon, strokes, vasculopathy, parenchymal calcifications, chilblains, and arthritis.

Chilblains

Figure 2. Magnetic resonance imaging performed 2 weeks later. A and B, New areas of diffusion restriction in the top panels with apparent diffusion coefficient (ADC) correlate (ADC images not shown), indicating new areas of infarct. C, Increased signal on fluid-attenuated inversion recovery images indicating infarcts of varying ages. D, Magnetic resonance angiogram image showing marked signal dropout in the anterior circulation at the terminus of the internal carotid arteries bilaterally.

analysis showed no oligoclonal bands, thyroglobulin antibodies of 32.5 IU/ml (normal value 0), and thyroid peroxidase antibodies of 6.7 IU/ml (normal value 0). His serum D-dimer was 1,622 ng/ml D-dimer units (normal value ⱕ232). The ESR was 7 mm/hour and the CRP level was ⬍0.30 mg/dl. A conventional cerebral angiogram was obtained and demonstrated stenoses of internal carotid arteries bilaterally with small-vessel collateralization of the bilateral middle cerebral, anterior cerebral, and posterior cerebral artery territories with the appearance of “puffs of smoke” consistent with moyamoya phenomenon (Figure 3). Multiple aneurysms were also seen in the distal distribution of the middle cerebral arteries bilaterally. No radiologic findings suggesting vasculitis, such as beading, were seen. The patient was given intravenous immunoglobulin (IVIG) for a presumed thyroid antibody– driven process, and he underwent a left craniotomy for anastomosis of the arterial intracranial arteries with encephalodurosynangiosis and microdissection.

The term chilblains is Anglo-Saxon in origin and combines the words “chill” and “blain” (a sore); perniosis is a Latin synonym. It is an inappropriate inflammatory reaction to cold and dampness, causing tender erythematous to purplish rash on the fingers, toes, and ears. It is postulated that trauma from cold induces injury from anoxia, which leads to a secondary inflammatory reaction (1). On histology, findings include small dermal vessels with endothelial edema and mononuclear perivascular infiltrate (2). Chilblains are classified into the following etiologies: idiopathic, autoimmune related, or drug induced. In the cold damp weather of the greater Cleveland area, it has been our experience that idiopathic chilblains occasionally occur in the pediatric population, and may be more frequent than in other locations in the US. Therefore, in our patient, it was possible that this was an unrelated problem; however, in light of his symptoms, other causes were explored. In children, predisposition to chilblains has been seen with cryoglobulins (3), anorexia nervosa (4), SLE (5), familial chilblain lupus (6), and Aicardi-Goutie`res syndrome (AGS) (7).

DIFFERENTIAL DIAGNOSIS The differential diagnosis in this patient was wide and evolved over his clinical course. On initial presentation, failure to thrive, speech delay, weakness, arthritis, and rash were the primary concerning problems. At that point, juvenile dermatomyositis, juvenile idiopathic arthritis, sarcoidosis, chilblains, systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), and hypothyroidism were considered. During his second outpatient visit, interim radiologic findings of brain calcifica-

Figure 3. Conventional intracranial angiogram images of the anterior circulation are shown in coronal and oblique views. The angiogram demonstrates the appearance of a “puff of smoke” at the carotid terminus bilaterally, consistent with moyamoya phenomenon. External carotid collateralization was also observed (not shown).

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MCTD During his first visit, MCTD was considered in our patient. In 1972, Sharp et al described MCTD in 25 patients who had a phenotypic mix of SLE, scleroderma, and polymyositis (8). The presence of anti–U1 nuclear RNP (nRNP) antibodies was suggested as part of the diagnostic criteria for the disease in adult patients (9). Our patient’s rash, weakness, and arthritis were concerning initially for MCTD. Later, with a positive anti–U1 nRNP antibody, MCTD remained on the differential diagnosis, but it did not explain all of his symptoms.

TORCH (toxoplasmosis, other infections [syphilis], rubella, cytomegalovirus [CMV] infection, and herpes simplex virus) infections Although we did not entertain a diagnosis of an active infectious process in our patient, we considered a previously undiagnosed congenital infection to explain the basal ganglia calcifications and the verbal delay. The memorable mnemonic of TORCH summarizes some of the pathogens that are typically seen in congenital intrauterine infections. Toxoplasmosis, rubella, and CMV can have associated calcifications that can appear identical to the findings in our patient (10).

Hypothyroidism and thyroid antibodies with encephalopathy and moyamoya Hashimoto encephalopathy is a syndrome associated with neurologic and psychiatric manifestations in conjunction with elevated antithyroid antibodies when other etiologies have been excluded (11). Clinical findings are intermittent or progressive; in the pediatric population, seizures, hemiparesis, altered mental status, depression, hallucinations, attention deficit, and learning difficulties have been described (12). In the setting of Hashimoto disease, there is a single pediatric case report describing CNS vasculitis (13). In our case, CNS vasculitis was considered in the differential diagnosis. Angiography can be used to diagnose CNS vasculitis, but it is not diagnostic. A brain biopsy is required to confirm the diagnosis. Li et al showed elevated thyroid function levels and antibodies in pediatric patients with moyamoya. Their study also showed a small percentage of patients with moyamoya that had decreased thyroid function; however, it was not statistically significant (14). Bilateral internal carotid artery stenosis and the development of multiple collaterals are described as moyamoya (“puff of smoke” or “misty” in Japanese) (15). Pediatric patients with moyamoya may develop strokes or epilepsy; adult patients are more likely to have hemorrhage (15).

DIAGNOSIS During the literature review, an article was found detailing genetic abnormalities associated with hypothyroidism and vasculopathy in the Amish population due to SAMHD1 gene mutation (16). This child had the homozygous c.1411-2A ⬎ G SAMHD1 gene mutation, which was described in the article. Although the authors of this study

Gurion et al

Table 1. Normal function in proteins involved in Aicardi-Goutie`res syndrome Gene name (chromosome location)

Normal function of encoded protein/ protein complex

TREX1 (3p21.31) AGS1

TREX1 protein is a 3⬘ repair exonuclease; it excises nucleotides to construct proper 3⬘ termini (22) RNASEH2B RNASEH2B, RNASEH2C, and (13q14.3) AGS2 RNASEH2A are the components of RNASEH2C RNase H2 complex (20) (proposed (11q13.2) AGS3 to cleave single ribonucleotides RNASEH2A from RNA:DNA duplexes [23] as (19p13.13) AGS4 well as lagging strand Okazaki fragment RNA primers [24]) SAMHD1 SAMHD1 is a dGTP-stimulated (20q11.23) AGS5 triphosphohydrolase; it converts deoxynucleoside triphosphates (dNTP) to deoxynucleoside and inorganic triphosphate (25) It is also postulated to decrease the dNTP concentration to a minimal level that does not support reverse transcription, thus preventing viral infections (26)

considered the SAMHD1 mutations to be an entity separate from AGS, others did not make this differentiation. Our further literature review supported a diagnosis of AGS in our patient.

DISCUSSION In 1984, Aicardi and Goutie`res described 8 children with symptoms that mimicked congenital infection. These symptoms included chronic CSF pleocytosis, progressive encephalopathy, and radiologic evidence of white matter hypodensities, encephalomalacia, and calcifications of the basal ganglia (17). In 1988, Lebon et al described elevated interferon-␣ (IFN␣) levels in AGS (18). Over the past 3 decades, further descriptions of AGS enhanced the collective understanding of the phenotypic and genetic spectrum of this syndrome. The prevalence of AGS is unknown. Currently, there are mutations in 5 genes that have been identified in causing approximately 90% of AGS: TREX1 (AGS1) (19); RNASEH2B (AGS2), RNASEH2C (AGS3), and RNASEH2A (AGS4) (20); and SAMHD1 (AGS5) (21). Normal function of these proteins is shown in Table 1. It is accepted that most individuals with AGS have the following features: calcifications of the basal ganglia, leukodystrophy, cerebral atrophy, and CSF abnormalities (leukocytosis, increased IFN␣, and neopterin) (7,27,28). Chilblains, mottling of skin, microcephaly in the first 12 months of life, dystonia, and sterile pyrexias are supportive of a diagnosis of AGS (7,27,28). There is a genotype– phenotype correlation where different gene mutations are more likely to produce certain phenotypic findings. RNASEH2B and SAMHD1 have milder phenotypic symptoms and a later presentation (7,29).

Clinicopathologic Conference The primary job of the immune system is to detect danger signals (30). When certain types of danger signals are detected, an inflammatory cascade driven by type I IFN is initiated. When it is targeted against an invader (such as viral nucleic acids) (31), it is a beneficial process; however, when responding to self–nucleic acids (following tissue injury [32] or with an imperfect clearance of self–nucleic acid [19]), it is a destructive process to self. IFN-stimulatory DNA response is one of the pathways that links detection of nucleic acids to an inflammatory process (31). TREX1 protein is a negative regulator of the IFN-stimulatory DNA response (33). It is responsible for removing cellular waste; when waste accumulates, an immune reaction is elicited (19). The discovery of TREX1 gene mutations elicited further understanding of the immune system. Apart from AGS (19), an improper TREX1 protein was reported in some patients with SLE (34) and familial chilblain lupus (6), retinal vasculopathy with cerebral leukodystrophy (35), and Cree encephalitis (36). In 2006, the 3 parts of the RNase H2 complex (RNASEH2B, RNASEH2C, and RNASEH2A) were identified in some AGS patients (20). Similar to TREX1, this complex is also involved in cellular debris removal (20,21). In 2009, SAMHD1 was found to be involved in AGS (21). SAMHD1 (the human homolog of murine IFN␥-induced gene MG11) is a 626 amino acid protein encoded by a 2283 bp messenger RNA (37). It was initially discovered in a human dendritic cell complementary DNA library, and was formerly termed dendritic cell– derived IFN␥-induced protein (37). Although the SAMHD1 protein is found in an array of tissues (37), it is expressed more often in dendritic cells and other cells of the myeloid line (38). SAMHD1 is a dGTP-stimulated triphosphohydrolase (25). It was shown to be up-regulated in response to viral infections (39), and was recently recognized to hinder human immunodeficiency virus type 1 infections in dendritic cells and macrophages (38,40), likely by degradation of DNA precursors (25). In addition to TREX1 and RNASEH2B, RNASEH2C, and RNASEH2A, SAMHD1 also plays a significant role in clearance of cellular waste and keeping IFN homeostasis (21). Of note, intracranial large-vessel stenosis, moyamoya, and aneurysms can be seen in individuals with SAMHD1 mutations (16,29,41), but have not been reported with any of the other gene mutations involved in AGS. Postmortem vasculitis of intracerebral and leptomeningeal vessels was reported in one patient (29). Arthritis has been reported with SAMHD1 mutation (16,41– 43), as well as clinical arthropathy and contractures (29,41,44). Several patients with SAMHD1 mutations were described with hypothyroidism (16,41), but this was also seen with TREX1 and RNASEH2B mutations (7). Aside from supportive care, there is no specific therapy for AGS. Further understanding of the genetic–immunologic pathogenesis of the disease, and in particular the IFN pathway, will likely change the therapeutic standard for this devastating disease. For the neurologic manifestations, Blau et al suggested therapy with oral folinic acid (45), but no studies were done to evaluate this. CSF IFN␣ level reduction was seen with the use of steroids; however, no further clinical im-

1543 provement was reported (46). High-dose corticosteroids or IVIG while experiencing elevated inflammatory markers and encephalitis did not alter the clinical course (47,48). Retroelement inhibitors were shown to improve myocarditis in TREX1-null mice, and were theorized to improve symptoms of AGS (49). A child with SAMHD1 mutation and moyamoya was considered a candidate for surgical revascularization; however, she had an intraventricular hemorrhage prior to the surgery and died (29). For the arthritis component of AGS, different therapies have been described. Ramantani et al described a patient with SAMHD1 mutation and arthritis treated with prednisone and azathioprine; the arthritis responded to therapy, but neurologic improvement was not reported (42). She also described another patient with SAMHD1 mutation who was treated with oral corticosteroids and naproxen for arthritis. Because of worsening of arthritis, a regimen of azathioprine and etanercept was initiated. Although the arthritis improved, the treatment did not treat the chilblains or neurologic disease (43). It is possible that the progressive decrease in CSF IFN␣ levels is the reason why immunosuppression has not been successful in treating the neurologic manifestations of AGS. If immunosuppression was started prior to permanent brain damage, patients might have a better outcome (43).

POSTHOSPITAL COURSE One month after discharge, the patient underwent rightsided superior temporal artery–middle cerebral artery bypass. His chilblains and arthritis resolved while receiving oral prednisolone, and he was weaned off of corticosteroids. Approximately 1 month after discontinuing steroid use, he was readmitted due to left upper extremity weakness and slurred speech, which were concerning for a stroke. An EEG showed changes consistent with recent craniotomy with no epileptiform discharges. At that time it was noted that his arthritis and chilblains were worse. He was restarted on prednisolone and methotrexate was added. On immunosuppression, his chilblains fully resolved and his arthritis significantly improved. A recent head CT scan following an accidental fall from a horse showed no new changes. Our patient’s laboratory findings are shown in Table 2.

Patient’s younger brother Our rheumatology service was recently consulted on our patient’s 1-month-old brother. He was born at 38 weeks gestational age via a cesarean section due to intrauterine growth restriction and a nonreassuring fetal heart rate. His mother’s prenatal screen was negative for VDRL, hepatitis B surface antigen, gonococcus, and chlamydia; she was immune to rubella, and was group B streptococci positive, for which she was treated. Apgar scores were 8 at 1 minute and 9 at 5 minutes. At approximately 6 hours of life, he had bilious emesis. He was admitted to the neonatal intensive care unit (NICU) and was evaluated for intestinal malrotation. His weight on admission to the NICU was 2,160 gm (less than third percentile), his head circumfer-

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Table 2. Patient’s laboratory findings*

Chemistry and muscle enzymes ALT, units/liter AST, units/liter Albumin, gm/dl CPK Aldolase Hematology CBC D-dimer, ng/ml DDU Urinalysis Inflammatory markers ESR, mm/hour CRP level Endocrinology CSF

3 months prior to the 2nd office visit

2nd office visit/ 1st admission

137 105 3.3

99 77

ATG antibodies, IU/ml TPO antibodies, IU/ml On admission TSH, mIU/liter FT4, ng/dl T3, ng/dl At discharge TSH, mIU/liter FT4, ng/dl Serologies ANA Anti-RNP, AI Anti-Ro, AI Anti–ribosomal P, AI TPO antibodies, IU/ml ATG antibodies, IU/ml Anti-dsDNA Lysozyme ANCAs ACE Infections Hepatitis panel CSF RBC count, cells/␮l WBC count, cells/␮l Total protein, mg/dl Culture Glucose Pathology Skin biopsy of left fifth toe

2nd admission

Normal value

10–65 10–60 3.4–5.1

WNL WNL WNL 1,622

ⱕ232

WNL WNL

0–13

WNL 41 WNL

No oligoclonal bands 32.5 6.7

0 0

730 0.19 49

0.36–3.74 0.6–1.5 100–275

230 1.03

0.36–3.74 0.6–1.5

1:160 Positive Positive Positive ⬎1,000 ⬎3,000 WNL WNL WNL WNL

Negative ⬍1 ⬍1 ⬍1 0–34 0

WNL 10,000 10 165 Negative Not obtained

0–5 15–45

Chilblains

* ALT ⫽ alanine aminotransferase; AST ⫽ aspartate transaminase; CPK ⫽ creatine phosphokinase; WNL ⫽ within normal limits; CBC ⫽ complete blood count; DDU ⫽ D-dimer units; ESR ⫽ erythrocyte sedimentation rate; CRP ⫽ C-reactive protein; CSF ⫽ cerebrospinal fluid; ATG ⫽ antithyroglobulin; TPO ⫽ thyroid peroxidase; TSH ⫽ thyroid-stimulating hormone; FT4 ⫽ free thyroxine; ANA ⫽ antinuclear antibody; AI ⫽ antibody index; anti-dsDNA ⫽ anti– double-stranded DNA antibody; ANCAs ⫽ antineutrophil cytoplasmic antibodies; ACE ⫽ angiotensin-converting enzyme; RBC ⫽ red blood cell; WBC ⫽ white blood cell.

ence was 33 cm (less than 25th percentile), and his length was 43.5 cm (less than third percentile). Physical examination was normal at that point except for mild bruising of the scalp, acrocyanosis, and mild distention of the abdomen. During the NICU course, abdominal pathology was ruled out; however, he developed feeding difficulties and irritability. An initial head ultrasound was normal. Sepsis eval-

uation was negative, and CMV urine antigen and blood CMV polymerase chain reaction were both negative. He developed thrombocytopenia and required platelet transfusion. He was also neutropenic and was found to have antineutrophil antibody, for which he received IVIG. A repeat head ultrasound obtained at approximately 1 month of life demonstrated bilateral lenticulostriate vasculopathy. MRI and MRA showed diffusely abnormal white mat-

Clinicopathologic Conference ter suggestive of a leukoencephalopathy and mild white matter volume loss, without evidence of acute ischemic injury, intracranial arterial vascular cutoff, stenosis, or dural sinus thrombosis. At the time of our consultation he was sedated and intubated for severe irritability, but his examination was otherwise normal. Knowing his brother’s diagnosis, he was tested for SAMHD1 mutation and was found to have an identical mutation. He was discharged home with supportive palliative care after 2 months of hospitalization. At an endocrinology outpatient appointment, he was found to have early primary hypothyroidism (TSH 10 mIU/liter). He was readmitted within 19 days of discharge secondary to worsening irritability, difficulty feeding, and dehydration. A head CT scan was obtained for concerns with altered mental status and showed abnormal hypoattenuation of periventricular white matter and punctate calcifications in bilateral basal ganglia periventricular white matter. He was discharged home on palliative supportive care. His family reports that he continues to have extreme irritability, is now fed via a nasogastric tube, and is not meeting his developmental milestones.

Parents and 7 other siblings Genetic testing was offered to the parents and 7 other siblings, but the family declined. Both parents are presumed to be heterozygotes for this mutation. None of the 7 older siblings or the parents display any symptoms concerning for AGS. Although the parents denied consanguinity, in the isolated Amish population it is probable that they share a distant common relative.

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Table 3. Phenotypic differences between the 2 brothers with identical c.1411-2A > G SAMHD1 mutations Older patient Reportedly normal pregnancy, birth, and infanthood Meeting all milestones except for verbal delays Proximal weakness Rash (chilblains) Arthritis Poor appetite Failure to thrive Brain calcifications, encephalomalacia, and moyamoya phenomenon Younger patient Small for gestational age Severe irritability at presentation Emesis at presentation Developmental delays notable early in development (not meeting expected milestones) Required placement of feeding tube to support nutrition Leukoencephalopathy and punctate calcifications in bilateral basal ganglia periventricular white matter No evidence for vascular involvement

full spectrum of phenotypic manifestations should be considered to be the same disease as the classic description of AGS (44,50) or considered an entirely different entity, as suggested by others (16). We believe that these are presentations within the same spectrum of disease. Perhaps in the future a different terminology will be used for the diagnosis of our 2 patients: “SAMHD1 mutation spectrum disorder.”

FINAL DIAGNOSIS CONCLUSION Discovering the genetic and immunopathologic basis of AGS has allowed for the further understanding of basic immune pathways involved in control of infectious and inflammatory disorders. The devastating phenotypic findings in the classic presentation of AGS demonstrate the delicate immunologic homeostasis required in the human body. Our older patient is unique because he received both immunosuppressive and surgical therapy. The immunosuppression is likely treating his articular and dermatologic manifestations, while the surgical therapy is responsible for his improved neurologic manifestations and prevention of further damage. We can only speculate whether his developmental delays were rooted in the neurologic manifestations of his AGS or in his severe hypothyroidism; likely it was a combination of both. His younger brother was treated with a single dose of IVIG. We did not offer subsequent immunosuppressive therapy, and we shall continue to wonder if his outcome would have been different if he had been given further immunosuppressive therapy. Although the 2 brothers had identical SAMHD1 gene mutations, their disease phenotype was different (Table 3). The phenotypic spectrum of AGS was described previously (44). A paradox of diagnosis occurs of whether the

Aicardi-Goutie`res syndrome caused by homozygous c.1411-2A ⬎ G SAMHD1 mutation for both patients. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Gurion had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Gurion, Nwankwo, Nanda, Brooks, Robinson. Acquisition of data. Gurion, Nwankwo, Nanda, Brooks, Mitchell, Wiznitzer, Robinson. Analysis and interpretation of data. Gurion, Nwankwo, Nanda, Brooks, Robinson.

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