Cohesin complex-associated holoprosencephaly.

Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80-90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly.

Mutations in LAMA1 cause cerebellar dysplasia and cysts with and without retinal dystrophy.

Cerebellar dysplasia with cysts (CDC) is an imaging finding typically seen in combination with cobblestone cortex and congenital muscular dystrophy in individuals with dystroglycanopathies. More recently, CDC was reported in seven children without neuromuscular involvement (Poretti-Boltshauser syndrome). Using a combination of homozygosity mapping and whole-exome sequencing, we identified biallelic mutations in LAMA1 as the cause of CDC in seven affected individuals (from five families) independent from those included in the phenotypic description of Poretti-Boltshauser syndrome. Most of these individuals also have high myopia, and some have retinal dystrophy and patchy increased T2-weighted fluid-attenuated inversion recovery (T2/FLAIR) signal in cortical white matter. In one additional family, we identified two siblings who have truncating LAMA1 mutations in combination with retinal dystrophy and mild cerebellar dysplasia without cysts, indicating that cysts are not an obligate feature associated with loss of LAMA1 function. This work expands the phenotypic spectrum associated with the lamininopathy disorders and highlights the tissue-specific roles played by different laminin-encoding genes.

Whole-genome analysis reveals that mutations in inositol polyphosphate phosphatase-like 1 cause opsismodysplasia.

Opsismodysplasia is a rare, autosomal-recessive skeletal dysplasia characterized by short stature, characteristic facial features, and in some cases severe renal phosphate wasting. We used linkage analysis and whole-genome sequencing of a consanguineous trio to discover that mutations in inositol polyphosphate phosphatase-like 1 (INPPL1) cause opsismodysplasia with or without renal phosphate wasting. Evaluation of 12 families with opsismodysplasia revealed that INPPL1 mutations explain ~60% of cases overall, including both of the families in our cohort with more than one affected child and 50% of the simplex cases.

Molecular analysis expands the spectrum of phenotypes associated with GLI3 mutations.

A range of phenotypes including Greig cephalopolysyndactyly and Pallister-Hall syndromes (GCPS, PHS) are caused by pathogenic mutation of the GLI3 gene. To characterize the clinical variability of GLI3 mutations, we present a subset of a cohort of 174 probands referred for GLI3 analysis. Eighty-one probands with typical GCPS or PHS were previously reported, and we report the remaining 93 probands here. This includes 19 probands (12 mutations) who fulfilled clinical criteria for GCPS or PHS, 48 probands (16 mutations) with features of GCPS or PHS but who did not meet the clinical criteria (sub-GCPS and sub-PHS), 21 probands (6 mutations) with features of PHS or GCPS and oral-facial-digital syndrome, and 5 probands (1 mutation) with nonsyndromic polydactyly. These data support previously identified genotype-phenotype correlations and demonstrate a more variable degree of severity than previously recognized. The finding of GLI3 mutations in patients with features of oral-facial-digital syndrome supports the observation that GLI3 interacts with cilia. We conclude that the phenotypic spectrum of GLI3 mutations is broader than that encompassed by the clinical diagnostic criteria, but the genotype-phenotype correlation persists. Individuals with features of either GCPS or PHS should be screened for mutations in GLI3 even if they do not fulfill clinical criteria.

Cerebellar ataxia with progressive improvement.

BACKGROUND: Nonprogressive cerebellar ataxias are characterized by a persistent, nonprogressive ataxia associated with cognitive impairment. Cerebellar hypoplasia on imaging is variable but is not predictive of the degree of ataxia or cognitive impairment. OBJECTIVE: To describe a family with a nonprogressive cerebellar ataxia associated with cognitive and motor impairments that improve with age. DESIGN: Genetic study in a family with nonprogressive cerebellar ataxia. Clinical and imaging features are also described. SETTING: Community hospital. PATIENTS: Both parents and 3 children from an affected family. MAIN OUTCOME MEASURES: Clinical features, magnetic resonance imaging findings, and genetic findings. RESULTS: A genome-wide single nucleotide polymorphism screen did not show clear linkage to known spinocerebellar ataxia loci, in particular spinocerebellar ataxia type 15. Repeat spinocerebellar ataxia loci expansions were excluded. Magnetic resonance images of all affected individuals demonstrated cerebellar vermian abnormalities. CONCLUSIONS: These findings suggest that nonprogressive cerebellar ataxia is genetically heterogeneous and, when associated with gradual improvement in cognition and motor skills, likely represents a separate, distinct clinical entity.

Endovascular treatment of spinal arteriovenous fistula in a young child with hereditary hemorrhagic telangiectasia. Case report.

Hereditary hemorrhagic telangiectasia ([HHT] or Osler-Weber-Rendu syndrome) can manifest as sudden onset of epistaxis or neurological deficit in a child with characteristic mucocutaneous telangiectasias or as an asymptomatic bruit with or without overlying cutaneous vascular lesions. The authors present a case study of a pediatric patient with HHT in whom a screening computerized tomography (CT) scan of the chest revealed an asymptomatic arteriovenous malformation (AVM) of the spine. An 18-month-old child with a strong family history of HHT, including fatal central nervous system (CNS) hemorrhage and pulmonary AVMs, presented with a cutaneous telangiectasia of the pinna. The child was subsequently screened for potentially morbid pulmonary and CNS AVMs by using chest CT scanning and brain magnetic resonance (MR) imaging. A spinal MR image revealed a perimedullary macro-AVF (MAVF) resulting in a large venous varix within the parenchyma of the thoracic spinal cord. A transarterial embolization of the fistula was performed using N-butyl cyanoacrylate and ethiodol. Postembolization angiography confirmed obliteration of the fistula, and MR imaging revealed thrombosis and reduction in size of the venous varix. There were no neurological sequelae due to the treatment. In families with HHT and a high risk of sudden severe morbidity or death from undisclosed pulmonary or CNS AVMs, screening chest CT scanning and CNS MR imaging should be considered. Interdisciplinary teams of neurosurgery and interventional radiology specialists should evaluate and treat such patients by using diagnostic and therapeutic angiography and, if necessary, surgery.

Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1.

BACKGROUND: Mutations in the gene encoding thyroid transcription factor, NKX2-1, result in neurologic abnormalities, hypothyroidism, and neonatal respiratory distress syndrome (RDS) that together are known as the brain-thyroid-lung syndrome. To characterize the spectrum of associated pulmonary phenotypes, we identified individuals with mutations in NKX2-1 whose primary manifestation was respiratory disease. METHODS: Retrospective and prospective approaches identified infants and children with unexplained diffuse lung disease for NKX2-1 sequencing. Histopathologic results and electron micrographs were assessed, and immunohistochemical analysis for surfactant-associated proteins was performed in a subset of 10 children for whom lung tissue was available. RESULTS: We identified 16 individuals with heterozygous missense, nonsense, and frameshift mutations and five individuals with heterozygous, whole-gene deletions of NKX2-1. Neonatal RDS was the presenting pulmonary phenotype in 16 individuals (76%), interstitial lung disease in four (19%), and pulmonary fibrosis in one adult family member. Altogether, 12 individuals (57%) had the full triad of neurologic, thyroid, and respiratory manifestations, but five (24%) had only pulmonary symptoms at the time of presentation. Recurrent respiratory infections were a prominent feature in nine subjects. Lung histopathology demonstrated evidence of disrupted surfactant homeostasis in the majority of cases, and at least five cases had evidence of disrupted lung growth. CONCLUSIONS: Patients with mutations in NKX2-1 may present with pulmonary manifestations in the newborn period or during childhood when thyroid or neurologic abnormalities are not apparent. Surfactant dysfunction and, in more severe cases, disrupted lung development are likely mechanisms for the respiratory disease.

Enchondroma of the skull base secondary to generalized enchondromatosis: a case report and review of the literature.

Generalized enchondromatosis, of which Ollier disease is the most common type, is a rare bone dysplasia characterized by multiple intraosseous tumors near growth-plate cartilage. These cartilaginous tumors have a propensity to transform into chondrosarcomas. Enchondromas of the skull base are exceedingly rare. We present the case of a patient with generalized enchondromatosis who developed a large enchondroma of the clivus, and we discuss the clinical presentation and potential treatments for this entity.

Selective IgM deficiency and 22q11.2 deletion syndrome.

BACKGROUND: The 22q11.2 deletion syndrome is a common chromosomal disorder with highly variable phenotypic expression and immunologic defects. Humoral immunity is mostly unaffected, but selective IgA deficiency occurs in up to 13% of patients. Selective IgM deficiency associated with 22q11.2 deletion has been reported in 1 patient. OBJECTIVE: To describe another 2 patients with 22q11.2 deletion syndrome and IgM deficiency. METHODS: Patient 1 was a 6-year-old boy with recurrent otitis media, sinopulmonary infections, wheezing, and speech delay. His serum IgM level was 18 mg/dL, and his IgA and IgG levels were normal. Antibody titers to protein and carbohydrate antigens were protective. Workup for velopharyngeal insufficiency resulted in the diagnosis of 22q11.2 deletion syndrome 3 years later. Patient 2 was a 14-year-old girl diagnosed as having 22q11.2 deletion at 9 years of age after presenting with neonatal seizures, atrial and ventricular septal defects, recurrent otitis media, mental retardation, and asthma. Her serum IgM level was 11 mg/dL, with normal IgG and IgA levels. Antibody titers to protein and carbohydrate antigens were protective. Patient 3 was a previously described 15-year-old girl with persistently draining ears, 22q11.2 deletion, and an IgM level less than 6 mg/dL. Her clinical and laboratory features are summarized. RESULTS: Results of further testing on the patients, including lymphocyte enumeration, were normal. The literature is reviewed regarding decreased IgM levels in 22q11.2 deletion syndrome. CONCLUSIONS: Fluorescence in situ hybridization analysis for chromosome 22q11.2 deletion should be considered in patients with selective IgM deficiency, especially if concurrent chronic otitis media, developmental delay, velopharyngeal insufficiency, or dysmorphic features are present.

A tribute to our teacher, Dr. Judith Hall: a child with the trait of the Earl of Shrewsbury.

"Organized human endeavor can be lifted an order of magnitude through teaching if it is inspiring" (Editor, Am J Dis Child, 1972). The benevolent influence of Dr. Judy Hall's inspiring clinical teaching in the field of genetic syndromes and birth defects is illustrated through the eventual surgical remediation of conductive hearing loss for a 4-year-old girl with unusual knuckles. The fascinating history of this child's syndrome has been further explored in the descendents of the first Earl of Shrewsbury. The legends of his story and his role in the Hundred Years War were immortalized by William Shakespeare in his play Henry VI Part I, but neither Shakespeare nor historians documented that the Earl actually had abnormal finger joints. Heterozygous mutations in the human noggin gene (NOG) cause a spectrum of joint fusions, including this child's traits. On behalf of practitioners of medicine, pediatrics, clinical genetics, and dysmorphology, as well as research scientists in the many domains of genetics, thank you, Judy, for your inspiration, enthusiasm, and teaching.