The Outcomes of an Individualized Physical Therapy Program in CALFAN Syndrome: A Case Report.

PURPOSE: This case report investigated the effectiveness of an individualized physical therapy program in CALFAN syndrome. CASE DESCRIPTION: A 13-year-old girl participated in physical therapy, which included trunk stabilization, balance training, and functional exercises for 12 weeks. ASSESSMENTS: The International Cooperative Ataxia Rating Scale; Trunk Impairment Scale; Pediatric Quality of Life Inventory; Functional Independence Measure for Children; Quick Disability of the Arm, Shoulder, and Hand Questionnaire; 9-Hole Peg Test; and Cobb measurement were used as outcome measures. RESULTS: Positive changes were observed in the International Cooperative Ataxia Rating Scale; Quick Disability of the Arm, Shoulder, and Hand Questionnaire; Pediatric Quality of Life Inventory; Trunk Impairment Scale; Functional Independence Measure; and the 9-Hole Peg Test. The Cobb angle was increased by 2° in the thoracic region and reduced by 11° in the lumbar region. CONCLUSIONS: Physical therapy improved quality of life, functional independence, trunk control, and upper extremity performance. WHAT THIS ADDS TO EVIDENCE: This case report is the first to support the effectiveness of physical therapy for a child with CALFAN syndrome.

Effectiveness of functional trunk training on trunk control and upper limb functions in patients with autosomal recessive hereditary ataxia.

BACKGROUND: Ataxia is a clinical syndrome characterized by coordination problems and postural disorders. OBJECTIVE: This study aimed to examine the effects of functional trunk training on trunk control and upper limb functions in autosomal recessive hereditary ataxia. METHODS: Twenty patients were randomly divided into treatment and control groups. Both groups received trunk stabilization and balance exercises, and the treatment group received additional functional trunk training sessions (3 days/week for 8 weeks). The International Cooperative Ataxia Rating Scale, Trunk Impairment Scale, Modified Functional Reach Test, Nine-Hole Peg Test and Quick-Disabilities of the Arm Shoulder and Hand questionnaire were used for assessments. RESULTS: The treatment group showed an increase in the upper limb performance bilaterally, whereas increased performance was seen only in the dominant upper limb in the control group. While the functional reach improved in the anterior-posterior (AP) and medial-lateral (ML) directions in the treatment group, it was improved only in the AP direction in the control group. Also, the mean changes in outcomes were not significantly different between the groups except for modified functional reach test. CONCLUSIONS: Functional trunk training may be a more effective method to improve upper limb performance and dynamic trunk balance in autosomal recessive hereditary ataxia.

SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling.

Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3) is a member of a small family of multifunctional cell surface-anchored glycoproteins functioning as co-receptors for a variety of growth factors. Here we report that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder. Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies. In vitro functional validation studies demonstrated a variable impact of disease-causing variants on transcript processing, protein secretion and function, and their dysregulating effect on bone morphogenetic protein (BMP) signaling. We show that SCUBE3 acts as a BMP2/BMP4 co-receptor, recruits the BMP receptor complexes into raft microdomains, and positively modulates signaling possibly by augmenting the specific interactions between BMPs and BMP type I receptors. Scube3-/- mice showed craniofacial and dental defects, reduced body size, and defective endochondral bone growth due to impaired BMP-mediated chondrogenesis and osteogenesis, recapitulating the human disorder. Our findings identify a human disease caused by defective function of a member of the SCUBE family, and link SCUBE3 to processes controlling growth, morphogenesis, and bone and teeth development through modulation of BMP signaling.

The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance.

Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.

Schwartz Jampel syndrome responding positively to carbamazepine therapy: a case report and a novel mutation.

Gürbüz G, Mutlu Albayrak H. Schwartz Jampel syndrome responding positively to carbamazepine therapy: a case report and a novel mutation. Turk J Pediatr 2019; 61: 967-970. Schwartz Jampel syndrome was first described in 1962. It is an autosomal recessive disease with generalized myotonic myopathy and skeletal dysplasia. A mutation in the HSPG2 gene occurs. Approximately 150 cases have been reported in literature. A 4-year-old girl presented to the pediatric neurology clinic due to difficulty in walking. The patient had difficulty opening her mouth and swallowing. She was unable to eat solid foods and was bottle fed. She was able to stand leaning forward, with her legs open and with one hand supported. Bilateral blepharospasm, posterior cleft palate, microstomia, pursed lips, kyphoscoliosis, contracture in the elbows, long thin fingers and campodactyly in the bilateral 5th fingers were present. Myotonic contraction with thenar percussion was observed. Previously undescribed mutation was determined in HSPG2 gene in the genetic study. Oral carbamazepine therapy was initiated and 1.5 months later the patient`s muscle rigidity had decreased and her motor skills had improved. This report contributes to the literature by defining a new mutation in HSPG2 gene and showing the importance of early diagnosis of the disease.

A congenital cranial dysinnervation disorder: Möbius' syndrome.

Möbius' syndrome, also known as Möbius' sequence, is a nonprogressive cranial dysinnervation disorder characterized by congenital facial and abducens nerve paralysis. Here, we report a 5-day-old girl who was conceived after in vitro fertilization with poor suck and facial paralysis. She had bilaterally ptosis and lateral gaze limitation, left-sided deviation of the tongue, dysmorphic face, hypoplastic fingers and finger nails on the left hand, and was diagnosed as having Möbius' syndrome. Involvement of other cranial nerves such as three, four, five, nine, 9 and 12, and limb malformations may accompany this syndrome. However, several factors have been proposed for the etiology, some rare cases have also been reported with artificial reproductive technologies. Feeding difficulties and aspiration are the main problems encountered in infancy. The other cranial nerves should be examined further in newborns who present with congenital facial palsy, and other cranial dysinnervation disorders should be considered in the differential diagnosis.