Laura Stewart

The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families.

Purpose:Truncating mutations in the maternally imprinted, paternally expressed gene MAGEL2, which is located in the Prader-Willi critical region 15q11–13, have recently been reported to cause Schaaf-Yang syndrome, a Prader-Willi-like disease that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties, and autism spectrum disorder. The causality of the reported variants in the context of the patients’ phenotypes was questioned, as MAGEL2 whole-gene deletions seem to cause little or no clinical phenotype.Methods:Here we report a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families, including 1 family with 3 individuals found to be affected with a truncating variant of MAGEL2, 11 individuals who are clinically affected but were not tested molecularly, and a presymptomatic fetal sibling carrying the pathogenic MAGEL2 variant.Results:All cases harbor truncating mutations of MAGEL2, and nucleotides c.1990–1996 arise as a mutational hotspot, with 10 individuals and 1 fetus harboring a c.1996dupC (p.Q666fs) mutation and 2 fetuses harboring a c.1996delC (p.Q666fs) mutation. The phenotypic spectrum of Schaaf-Yang syndrome ranges from fetal akinesia to neurobehavioral disease and contractures of the small finger joints.Conclusion:This study provides strong evidence for the pathogenicity of truncating mutations of the paternal allele of MAGEL2, refines the associated clinical phenotypes, and highlights implications for genetic counseling for affected families.Genet Med 19 1, 45–52.

Pseudohypoparathyroidism type 1a and the GNAS p.R231H mutation: Somatic mosaicism in a mother with two affected sons†

Pseudohypoparathyrodism (PHP) is a disorder caused by mutations in the guanine nucleotide‐binding α‐subunit (GNAS). We sought to determine the genetic origin of PHP1a in one affected family. We identified the previously reported Gsα R231H mutation in family members affected with PHP1a. DNA analysis found that the two clinically affected sons are heterozygous for the mutation. The sons have PHP1a, manifesting obesity, intellectual disability, hypogonadism, hypothyroidism and elevated PTH levels. Initial DNA sequencing did not detect the mutation in either parent. However, their mother displayed some features of PHP, including elevated PTH levels and asymmetrical metacarpal shortening. Using molecular cloning, we detected the mutation at low levels in the mothers leukocyte DNA, consistent with somatic mosaicism and her mildly affected status. Thus, we have identified additional cases of PHP1a caused by the Gsα R231H mutation. In this family, the mother has a milder phenotype due in part to somatic mosaicism, whereas the two affected sons have full PHP1a. Though somatic mosaicism for activating GNAS mutations is known to occur in McCune–Albright syndrome, this is the first report confirming somatic mosaicism for a hypofunctioning GNAS mutation in a PHP kindred.

Hyperthyroidism hidden by congenital central hypoventilation syndrome.

Abstract Congenital central hypoventilation syndrome (CCHS) is a rare neurocristopathy with severe central hypoventilation. CCHS results from a mutation in the paired-like homeobox 2B gene (PHOX2B). In addition to hypoventilation, patients with CCHS display a wide array of autonomic nervous system abnormalities, including decreased heart rate variability and abrupt sinus pauses, esophageal dysmotility, abnormal pupillary light response, and temperature dysregulation, to name a few. To date, there has been no documentation of a child with both CCHS and hyperthyroidism. We report the case of a young child with CCHS who presented with tachycardia, which was later found to be due to Grave’s disease, after many months of investigation.

Long Term Medical Treatment of Congenital Hyperinsulinemic Hypoglycemia

Background: Hyperinsulinism is the most common cause of recurrent Hypoglycemia in early infancy. Surgical treatment with partial/near total pancreatectomy has been the mainstay of treatment but does not result in complete remission of Hypoglycemia and is associated with high risk of diabetes mellitus Design and methods: We retrospectively reviewed 23 patients (1979-2009) with congenital hyperinsulinism treated medically and surgically. Patients are divided in three groups: 1) treated with diazoxide 2) treated with octreotide alone or along with diazoxide 3) treated with surgical resection. Main outcomes measured are prevention of Hypoglycemia, treatment side effects, onset of diabetes mellitus and effects on growth. Results: Eight patients were treated with diazoxide, 10 with octreotide alone or along with diazoxide and 5 had surgical resection. Four patients came off diazoxide between 5.5-10.5 years age, 3 are less than 5 years and still on treatment. Two patients came off octreotide at 5.5 and 7 years and six remain on treatment with their ages between 6 months and 12 years. No patient could come off medical treatment after surgical resection. 2 patients had diabetes in surgical group and none in medical group. Conclusion: Medical therapy with diazoxide, octreotide, glucagon and extensive feeding plan is an effective treatment for control of Hypoglycemia in congenital hyperinsulinism patients.