Heterotopic ossifications and Charcot joints: Congenital insensitivity to pain with anhidrosis (CIPA) and a novel NTRK1 gene mutation.

Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV (HSAN-IV), is a rare and severe autosomal recessive disorder. We report on an adult female patient whose clinical findings during childhood were not recognized as CIPA. There was neither complete anhidrosis nor a recognizable sensitivity to heat. Tumorlike swellings of many joints and skeletal signs of Charcot neuropathy developed in adolescence which, together with a history of self-mutilation, led to a clinical suspicion of CIPA confirmed by identification of a novel homozygous variant c.1795G > T in the NTRK1 gene in blood lymphocytes. Both parents were heterozygous for the mutation. The variant predicts a premature stop codon (p.Gly599Ter) and thus represents a pathogenic variant; the first reported in the Southeastern European population.

Severe digital malformations in a rare variant of fibrodysplasia ossificans progressiva.

A 16-year-old girl with a history of nontraumatic swelling of both forearms, osteochondromas of the knees, heterotopic ossification of the neck and back, severe malformations of all digits with hypoplastic or absent nails, alopecia partialis of the scalp, and moderate cognitive impairment was seen for diagnostic evaluation. Whole exome sequencing identified an activating mutation of ACVR1 (c.983G > A; p.Gly328Glu) which confirmed a suspected FOP variant. The delayed diagnosis of an FOP variant in this patient could have been avoided if the significance of severe digital malformations had been recognized, especially in the setting of progressive heterotopic ossification.

IGF1R Gene Alterations in Children Born Small for Gestitional Age (SGA).

BACKGROUND: Small for gestational age (SGA)-born children are a heterogeneous group with few genetic causes reported. Genetic alterations in the IGF1 receptor (IGF1R) are found in some SGA children. AIM: To investigate whether alterations in IGF1R gene are present in SGA born children. PATIENTS AND METHODS: We analysed 64 children born SGA who stayed short (mean -3.25 ± 0.9 SDS) within the first 4 years of age, and 36 SGA children who caught up growth (0.20 ± 1.1 SDS). PCR products of all coding IGF1R exons were screened by dHPLC followed by direct sequencing of conspicuous fragments to identify small nucleotide variants. The presence of IGF1R gene copy number alterations was determined by Multiplex Ligation-dependent Probe Amplification (MLPA). RESULTS: The cohort of short SGA born children revealed a heterozygous, synonymous variant c.3453C > T in one patient and a novel heterozygous 3 bp in-frame deletion (c.3234_3236delCAT) resulting in one amino acid deletion (p.Ile1078del) in another patient. The first patient had normal serum levels of IGF1. The second patient had unusually low IGF1 serum concentrations (-1.57 SD), which contrasts previously published data where IGF1 levels rarely are found below the age-adjusted mean. CONCLUSIONS: IGF1R gene alterations were present in 2 of 64 short SGA children. The patients did not have any dysmorphic features or developmental delay. It is remarkable that one of them had significantly decreased serum concentrations of IGF1. Growth response to GH treatment in one of the patients was favourable, while the second one discontinued the treatment, but with catch-up growth.

A 4-Year-Old Boy with Beckwith Wiedemann Syndrome (BWS).

OBJECTIVES: Molecular characterization of a patient with BWS. CLINICAL PRESENTATION AND INTERVENTION: A 4-year-old boy with overgrowth (weight above 99th and height at 99th percentile) had longitudinal hemihypertrophy of the tongue and left cheek. In addition, there was a difference of one centimeter in the circumference of the left and right leg. Molecular genetic analysis revealed hypomethylation of KvDRM1 (LIT1) in the imprinting control region-2 (ICR2) on chromosome 11p15.5 and a normal methylation pattern of the H19-differentially methylated region (H19-DMR) in the ICR1. The estimated tumor risk was 1-5%. CONCLUSION: This patient with clinical characteristics of BWS has an imprinting defect associated with a low risk of embryonal tumors.

LHX4 Gene Alterations: Patient Report and Review of the Literature.

LHX4 mutations are rare in combined pituitary hormone deficiency, and even rarer in isolated GHD. We describe a 14 years old boy who was referred for investigation of short stature. Convergent strabismus, nystagmus was present. At the age of 5 years his gait was unstable. A progressive myopathy ensued. Tests of pituitary reserve showed partial IGHD (8.2 ng/ml). Other pituitary hormones were within normal range. Muscle biopsy showed congenital myopathy of undefined etiology. MRI of the brain revealed the empty sella syndrome. Targeted resequencing with a panel containing probe sets for enrichment and analysis of > 4,800 clinically relevant genes, targeting 12Mb of the human genome revealed the c.250C>T (R84C) LHX4 mutation. His father is healthy, with no myopathy or pituitary deficiencies, but has the same LHX4 mutation. This report extends the range of phenotypes associated with LHX4 gene mutations. To the best of our knowledge, we are the first to report on congenital myopathy in an LHX4 gene mutation. Forthwith, we offer a comprehensive review of the patients published so far with their clinical and genetic characteristics.

Congenital erythropoietic porphyria with two mutations of the uroporphyrinogen III synthase gene (Cys73Arg, Thr228Met).

Congenital erythropoietic porphyria (CEP) is an autosomal recessive inborn error of metabolism that results from the markedly deficient activity of uroporphyrinogen III synthase (UROS). We describe a 14-year-old girl with red urine since infancy, progressive blistering and scarring of the skin, and moderate hemolytic anemia. After years of skin damage, her face is mutilated; she has a bald patch on the scalp, hypertrichosis of the neck, areas of skin darkening, and limited joint movements of the hands. Total urine excretion and fecal total porphyrin were both markedly raised above normal levels. Sequencing of the UROS gene identified two mutations causing CEP (Cys73Arg, Thr228Met). The patient lesions are progressing. Bone marrow transplantation and/or gene therapy are proposed as the next steps in her treatment. In brief, we describe a CEP with confirmed two pathogenic mutations, severe phenotype and discuss the various treatment options available.

Billateral polycystic kidneys in a girl with WAGR syndrome.

The WAGR contiguous gene deletion syndrome is a combination of Wilms tumor, aniridia, genito-urinary abnormalities, and mental retardation. An 8.5-year-old girl was initially investigated at the age of 18 months for congenital bilateral aniridia, cataracts, glaucoma and epicantus. The ultrasound (US) scan showed polycystic kidney disease. FISH study revealed deletion of the WT1 and PAX6 gene in the 11p13 WAGR region. Forty days after the first kidney US, the second US revealed a 3 cm tumor in the right kidney: a Wilms tumour, treated successfully with the Wilm's tumor protocol. The authors conclude that the identification of the deletions in the WAGR region in patients with aniridia should definitely be done. In addition, Wilms tumor can have a very rapid growth, which, per se requires frequent and careful ultrasound kidney controls. Polycystic kidneys can be part of the WAGR presentation.