PDE3A variant associated with hypertension and brachydactyly syndrome in a patient with ischemic stroke caused by spontaneous intracranial artery dissection: A review of the clinical and molecular genetic features.

Hypertension and brachydactyly syndrome (HTNB; MIM 112410) is a rare, recently described, autosomal dominant syndromic disease characterized by the triad of brachydactyly type E (BDE), short stature, and hypertension. HTNB is caused by a heterozygous mutation in the PDE3A (MIM 123805) gene on chromosome 12p12; this gene encodes a member of the cGMP-inhibited cyclic nucleotide phosphodiesterase family. PED3A plays a role in many signal transduction pathways, including those involved in vascular smooth muscle proliferation and contraction, cardiac contractility, platelet aggregation, and hormone secretion. Here, we present a new case of HTNB in a 42-year-old patient who experienced recurrent ischemic strokes in various vascular territories; these strokes were caused by intracranial multiarterial dissection, and were experienced for 2 weeks. She was found to harbor a de novo heterozygous in-frame deletion, c.1333_1335del p.(Thr445del), in exon 4 of the PDE3A gene. Our finding is expected to contribute to the elucidation of the pathophysiology of stroke in HTNB patients. We further review all clinical and molecular genetic features of this rare disease described in the literature to date.

[A rare type of severe obesity in children and adolescents].

A four-year-old girl was referred to a paediatric department with low height, obesity and hypothyroidism. Her paraclinical tests were characteristic with elevated P-parathyroid hormone concentration, hypothyroidism, growth hormone deficiency, abnormal phenotype with brachydactyly, tooth problems and mental retardation, which led to a suspicion of Albright's hereditary osteodystrophy (AHO). The diagnosis was verified by molecular genetic testing. Less than 1% of children with obesity have an endocrine disorder, and AHO is one of them.

Symbrachydactyly.

Background: Symbrachydactyly is a unilateral congenital hand malformation characterized by failure of formation of fingers and the presence of rudimentary digit nubbins. The management is variable and are investigated in this review. Methods: A detailed review of the literature was compiled into succinct clinically relevant categories. Results: Etiology, classification, non-surgical management, surgical intervention, and patient oriented outcomes are discussed. Conclusions: All interventions should prioritize realistic, evidence-supported appearance and functional gains. Studies of the baseline function and quality of life of children with symbrachydactyly would allow surgeons to better understand functional changes associated with various interventions and would help surgeons and parents to make the best treatment decisions.

Otofaciocervical syndrome and metachondromatosis in a girl: Presentation of a novel association and remarks on clinical variability of branchial-arch disorders.

Otofaciocervical syndrome (OFCS) is a rare disorder characterized by facial, ear, branchial, and musculoskeletal anomalies, along with hearing loss and mild intellectual disability. Clinically, its distinction from branchiootorenal syndrome can be difficult. To date, the coexistence of OFCS and metachondromatosis has not been reported. Here, we describe a sporadic patient with both OFCS and metachondromatosis. This novel association prompts us to do some remarks on the clinical variability of branchial-arch disorders; in fact, our observations are consistent with the highly variable expressivity of OFCS and illustrate the need of a more accurate characterization of these branchial-arch disorders. In the meantime, involvement of clavicles, scapulae and shoulders remains a distinctive feature of OFCS.

Abnormal layering of muscularis propria as a cause of chronic intestinal pseudo-obstruction: A case report and literature review.

Visceral myopathy is one of the causes of chronic intestinal pseudo-obstruction. Most cases pathologically reveal degenerative changes of myocytes or muscularis propia atrophy and fibrosis. Abnormal layering of muscularis propria is extremely rare. We report a case of a 9-mo-old Thai male baby who presented with chronic intestinal pseudo-obstruction. Histologic findings showed abnormal layering of small intestinal muscularis propria with an additional oblique layer and aberrant muscularization in serosa. The patient also had a short small bowel without malrotation, brachydactyly, and absence of the 2(nd) to 4(th) middle phalanges of both hands. The patient was treated with cisapride and combined parenteral and enteral nutritional support. He had gradual clinical improvement and gained body weight. Subsequently, the parenteral nutrition was discontinued. The previously reported cases are reviewed and discussed.

Functional analysis of alleged NOGGIN mutation G92E disproves its pathogenic relevance.

We identified an amino acid change (p.G92E) in the Bone Morphogenetic Protein antagonist NOGGIN in a 22-month-old boy who presented with a unilateral brachydactyly type B phenotype. Brachydactyly type B is a skeletal malformation that has been associated with increased Bone Morphogenetic Protein pathway activation in other patients. Previously, the amino acid change p.G92E in NOGGIN was described as causing fibrodysplasia ossificans progressiva, a rare genetic disorder characterized by limb malformations and progressive heterotopic bone formation in soft tissues that, like Brachydactyly type B, is caused by increased activation of Bone Morphogenetic Protein signaling. To determine whether G92E-NOGGIN shows impaired antagonism that could lead to increased Bone Morphogenetic Protein signaling, we performed functional assays to evaluate inhibition of BMP signaling. Interestingly, wt-NOGGIN shows different inhibition efficacies towards various Bone Morphogenetic Proteins that are known to be essential in limb development. However, comparing the biological activity of G92E-NOGGIN with wt-NOGGIN, we observed that G92E-NOGGIN inhibits activation of bone morphogenetic protein signaling with equal efficiency as wt-NOGGIN, supporting that G92E-NOGGIN does not cause pathological effects. Genetic testing of the child's parents revealed the same amino acid change in the healthy father, further supporting that p.G92E is a neutral amino acid substitution in NOGGIN. We conclude that p.G92E represents a rare polymorphism of the NOGGIN gene-- causing neither brachydactyly nor fibrodysplasia ossificans progressiva. This study highlights that a given genetic variation should not be considered pathogenic unless supported by functional analyses.

Brachydactylia as a phenotypic feature of mitochondrial disorder.

Mitochondrial disorders (MIDs) may occasionaly go along with dysmorphism but hand deformities, as in the following case, have been only rarely reported. A 72 year old female with ptosis, hypoacusis, tremor, myopathy, diabetes mellitus, arterial hypertension, severe cardiac disease, pulmonary hypertension, gastric carcinoid, hepatopathy, generalised atherosclerosis, anemia, polyarthrosis, and hyperlipidemia, additionally presented with brachydactylia. Upon neurological work-up a MID was suspected. The family history was positive for diabetes but negative for brachydactylia or other features of a MID. MIDs may be associated with brachydactylia. Skeletal deformities may be a phenotypic manifestation of MIDs.