Jewell C. Ward

Allan-Herndon-Dudley Syndrome and the Monocarboxylate Transporter 8 (MCT8) Gene

Allan-Herndon-Dudley syndrome was among the first of the X-linked mental retardation syndromes to be described (in 1944) and among the first to be regionally mapped on the X chromosome (in 1990). Six large families with the syndrome have been identified, and linkage studies have placed the gene locus in Xq13.2. Mutations in the monocarboxylate transporter 8 gene (MCT8) have been found in each of the six families. One essential function of the protein encoded by this gene appears to be the transport of triiodothyronine into neurons. Abnormal transporter function is reflected in elevated free triiodothyronine and lowered free thyroxine levels in the blood. Infancy and childhood in the Allan-Herndon-Dudley syndrome are marked by hypotonia, weakness, reduced muscle mass, and delay of developmental milestones. Facial manifestations are not distinctive, but the face tends to be elongated with bifrontal narrowing, and the ears are often simply formed or cupped. Some patients have myopathic facies. Generalized weakness is manifested by excessive drooling, forward positioning of the head and neck, failure to ambulate independently, or ataxia in those who do ambulate. Speech is dysarthric or absent altogether. Hypotonia gives way in adult life to spasticity. The hands exhibit dystonic and athetoid posturing and fisting. Cognitive development is severely impaired. No major malformations occur, intrauterine growth is not impaired, and head circumference and genital development are usually normal. Behavior tends to be passive, with little evidence of aggressive or disruptive behavior. Although clinical signs of thyroid dysfunction are usually absent in affected males, the disturbances in blood levels of thyroid hormones suggest the possibility of systematic detection through screening of high-risk populations.

CRTAP AND LEPRE1 MUTATIONS IN RECESSIVE OSTEOGENESIS IMPERFECTA

Autosomal dominant osteogenesis imperfecta (OI) is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen. Recently, dysregulation of hydroxylation of a single proline residue at position 986 of both the triple‐helical domains of type I collagen α1(I) and type II collagen α1(II) chains has been implicated in the pathogenesis of recessive forms of OI. Two proteins, cartilage‐associated protein (CRTAP) and prolyl‐3‐hydroxylase‐1 (P3H1, encoded by the LEPRE1 gene) form a complex that performs the hydroxylation and brings the prolyl cis‐trans isomerase cyclophilin‐B (CYPB) to the unfolded collagen. In our screen of 78 subjects diagnosed with OI type II or III, we identified three probands with mutations in CRTAP and 16 with mutations in LEPRE1. The latter group includes a mutation in patients from the Irish Traveller population, a genetically isolated community with increased incidence of OI. The clinical features resulting from CRTAP or LEPRE1 loss of function mutations were difficult to distinguish at birth. Infants in both groups had multiple fractures, decreased bone modeling (affecting especially the femurs), and extremely low bone mineral density. Interestingly, “popcorn” epiphyses may reflect underlying cartilaginous and bone dysplasia in this form of OI. These results expand the range of CRTAP/LEPRE1 mutations that result in recessive OI and emphasize the importance of distinguishing recurrence of severe OI of recessive inheritance from those that result from parental germline mosaicism for COL1A1 or COL1A2 mutations. Hum Mutat 0, 1–8, 2008.

Effect of beta-adrenergic blockade on aortic root rate of dilation in the Marfan syndrome

Abstract We recommend that patients with the Marfan syndrome should begin P-adrenergic blocker therapy at the earliest age possible and that the dose be adjusted to the largest dose that is clinically tolerated. Our centers differ with respect to the size of the aorta at the time of recommending onset of therapy. The JHH criteria do not include a size cutoff. The UT experience and recommendation is to treat children with aortic size at or above the 95th percentile.

Neonatal progeroid (Wiedemann-Rautenstrauch) syndrome: Report of five new cases and review

The neonatal progeroid syndrome (NPS), or Wiedemann-Rautenstrauch, is a rare autosomal recessive disorder comprised of generalized lipoatrophy except for fat pads in the suprabuttock areas, hypotrichosis of the scalp hair, eyebrows, and eyelashes, relative macrocephaly, triangular face, natal teeth, and micrognathia. We report on 5 new patients who demonstrate phenotypic variability and who represent the single largest series of NPS reported to date. Two of the patients are from an African-American kindred, an ethnic occurrence not reported previously. The fact that there are 2 pairs of sibs among the 5 patients further supports that NPS is an autosomal recessive condition. This report also includes a review of the previously reported 16 patients and compares them with the 5 new patients. Abnormalities in endocrine and lipid metabolism were found in 3 of 5 patients. Skeletal findings in 2 of our patients demonstrated some new findings as well as the typical radiological abnormalities previously noted in NPS. It is apparent, based on the 21 cases, that mild to moderate mental retardation is common in NPS. Long term follow-up of patients with NPS should provide more information relative to their ultimate psychomotor development. NPS is usually lethal by 7 months; however, on rare occasions, patients have survived into the teens. Our 3 surviving patients range in age from 16-23 months. Variability in the phenotype of NPS is clear; however, the phenotype remains distinct enough to allow a secure diagnosis.

Deletion and duplication of 15q24: Molecular mechanisms and potential modification by additional copy number variants

Purpose: To investigate the potential influence of additional copy number variants in patients with 15q24 rearrangements and the possible underlying mechanisms for these rearrangements.Methods: Oligonucleotide-based chromosomal microarray analyses were performed, and the results were subsequently confirmed by fluorescence in situ hybridization analyses. Long-range polymerase chain reaction amplification and DNA sequencing analysis were used for breakpoint junction sequencing.Results: We describe a 15-year-old boy with cognitive impairment and dysmorphic features with deletions in 15q24 and 3q21, a 2-month-old female infant with growth deficiency, heterotaxy, cardiovascular malformations, intestinal atresia, and duplications in 15q24 and 16q22, and a 3.5-year-old boy with developmental delay, microcephaly, and dysmorphic features, with duplications in 15q24 and 2q36.3q37.1. Breakpoint sequencing for the 15q24 deletion in the first patient revealed microhomology and suggested the underlying mechanism of either nonhomologous end joining or fork stalling and template switching/microhomology-mediated break-induced replication.Conclusions: The three described patients with 15q24 rearrangements have copy number variants at other loci and exhibit additional clinical features with a more severe phenotype than that observed in previously reported patients with isolated 15q24 rearrangements, suggesting that the genomic mutational load may contribute to the phenotypic severity and variability in patients with 15q24 rearrangements.

Propionic acidaemia and immunodeficiency

identical with those in previous reports (Holt et al 1990; Tatuch et al 1992). Early onset of the disease and rapid progression with death during the first year of life were also present in three of four patients of the pedigree described by Tatuch et al (1992). Later onset of the disease and prolonged survival of two patients described by Ciafaloni et al (1993) and one patient of Holt et al (1990) resemble the clinical course of the probands brother. Retinopathy observed in the case of his sister seems to be quite unusual for her age, although it is typically present in older patients with this mutation. Degeneration of basal ganglia and brainstem, typically present in published patients with early onset of the disease, was no t revealed in our patient and his brother. Detailed examination of the muscle of our patient revealed no ragged red fibres and is in agreement with results in previous patients.

Case report of a young child with disseminated histoplasmosis and review of hyper immunoglobulin e syndrome (HIES)

Type 1 hyper IgE syndrome (HIES), also known as Jobs Syndrome, is an autosomal dominant disorder due to defects in STAT3 signaling and Th17 differentiation. Symptoms may present during infancy but diagnosis is often made in childhood or later. HIES is characterized by immunologic and non-immunologic findings such as recurrent sinopulmonary infections, recurrent skin infections, multiple fractures, atopic dermatitis and characteristic facies. These manifestations are accompanied by elevated IgE levels and reduced IL-17 producing CD3+CD4+ T cells. Diagnosis in young children can be challenging as symptoms accumulate over time along with confounding clinical dilemmas. A NIH clinical HIES scoring system was developed in 1999, and a more recent scoring system with fewer but more pathogonomonic clinical findings was reported in 2010. These scoring systems can be used as tools to help in grading the likelihood of HIES diagnosis. We report a young child ultimately presenting with disseminated histoplasmosis and a novel STAT3 variant in the SH2 domain.

Markedly elevated serum biotinidase activity may indicate glycogen storage disease type Ia

Summary: We report two children who presented with symptoms suggestive of biotinidase deficiency. Rather than deficiency, markedly elevated serum biotinidase activities were found. Based upon literature reports of elevated biotinidase activities in children with glycogen storage disease (GSD) type Ia, we considered the latter in our differential diagnosis and subsequently confirmed GSD type Ia in both patients by enzymatic testing. GSD type Ia should be considered in children with markedly elevated serum biotinidase activity.

Novel genome-wide associations for suicidality in UK Biobank, genetic correlation with psychiatric disorders and polygenic association with completed suicide.

Background: Suicide is a major issue for global public health. ‘Suicidality’ describes a broad clinical spectrum of thoughts and behaviours, some of which are common in the general population. Methods: UK Biobank recruited ∼0·5 million middle age individuals from the UK, of whom 157,000 completed an assessment of suicidality. Mutually exclusive groups were assessed in an ordinal genome-wide association study of suicidality: ‘no suicidality’ controls (N=83,557); ‘thoughts that life was not worth living’ (N=21,063); ‘ever contemplated self-harm’ (N=13,038); ‘an act of deliberate self-harm in the past’ (N=2,498); and ‘a previous suicide attempt’ (N=2,666). Linkage of UK Biobank to death certification records identified a small sub-group of ‘completed suicide’ (N=137). Outcomes: We identified three novel genome-wide significant loci for suicidality (on Chromosomes 9, 11 and 13) and moderate-to-strong genetic correlations between suicidality and a range of psychiatric disorders, most notably depression (rg 0·81). Higher polygenic risk scores for suicidality were associated with increased risk of completed suicide relative to controls in an independent sub-group (N=137 vs N=5,330, OR 1·23, 95%CI 1·06 to 1·41, p=0.03). Rs598046-G (chromosome 11) demonstrated a similar effect size and direction (p=0·05) within a Danish suicidality study. Interpretation: These findings have significant implications for our understanding of genetic vulnerability to suicidal thoughts and behaviours. Future work should assess the extent to which polygenic risk scores for suicidality, in combination with non-genetic risk factors, may be useful for stratified approaches to suicide prevention at a population level. Funding: UKRI Innovation-HDR-UK Fellowship (MR/S003061/1). MRC Mental Health Data Pathfinder Award (MC_PC_17217).

Genitopatellar syndrome and neuroblastoma: The multidisciplinary management of a previously unreported association

To the Editor: Genitopatellar syndrome (GPS) is an autosomal dominant disorder resulting from inherited or de novo heterozygous truncating mutations of the lysine acetyltransferase 2B (KAT6B) gene.1 GPS is characterized by skeletal dysplasia, urogenital anomalies, craniofacial defects, and intellectual disabilities.2 Specific features include agenesis of the corpus callosum, microcephaly, psychomotor impairment, hydronephrosis, scrotal hypoplasia, cryptorchidism, renal cysts, dental anomalies, anal anomalies, congenital contractures of the lower limbs, and its namesake patellar hypoplasia/agenesis.3 KAT6B was recently shown to act as a tumor suppressor, whereby homozygous deletions were associated with the development and progression of small cell lung cancer.4 We present a 17-month-old male child who is the 17th case of GPS reported in the literature and the first reportedGPS patient to be diagnosedwith neuroblastoma.1–3,5–13 The patient presented at birth with features of GPS includes extremity deformities, facial dysmorphism, bilateral cryptorchidism, absent corpus callosum and anterior commissure, and severe gastroesophageal reflux disorder (Supporting Information Figure S1). The patient was found to have a germline heterozygous nonsense variant in the KAT6B gene [NM_012330.3:c.3736C > T (p.Gln1246*)]. At 17 months of age, the patient underwent abdominal computed tomography (CT) scan for progressive abdominal distension and discomfort. The CT scan identified a 6.8 cm, partially calcified right suprarenal mass extending along the portal vein and displacing the inferior vena cava anteriorly (Figure 1). The colon was massively dilated to the level of the anus without a discrete transition point (Figure 1). Metaiodobenzylguanidine uptake was limited to the suprarenal mass, and random urine vanillylmandelic and homovanillic acid levels were elevated, strongly suggesting a neuroblastic tumor. Bone marrow biopsy and aspirates were negative for metastatic disease. The patient was judged preoperatively to be INRG low risk due to his age (<18months), L2 lesion (extension along the porta hepatis), presumed MYCN nonamplified status, and absence of metastases. Therefore, the initial management plan consisted of primary surgical resection of the tumor. Close perineal examination revealed severe anal stenosis as the likely cause of his colonic dilation. A contrast enema and rectal biopsy excluded Hirschprung disease. An anoplasty was performed with significant improvement in his colonic dilation and ability to stool (Supporting Information Figure S1). Seven days later, the patient underwent right radical adrenalectomy (Figure 1). A gross total resection of the right adrenal gland and retroperitoneal mass was performed. Based on his previously diagnosed bilateral cryptorchidism, the first of the two stage Fowler-Stephens procedure was performed by dividing the gonadal vessels on each side. F IGURE 1 (A) Preoperative CT scan demonstrated a right adrenal neuroblastoma and amassively dilated colon (Co). The tumor was located between the portal vein (right portal vein—white arrow; main portal vein—dashed arrow), the inferior vena cava (asterix), the aorta (black arrow), and the celiac axis (ca). (B) The inferior vena cava (blue vessel loops) was dissected off the anterior surface of the tumor (asterix)