FKBP14 kyphoscoliotic Ehlers-Danlos syndrome misdiagnosed as Larsen syndrome: a case report.

Hereditary connective tissue disorders have overlapping phenotypes, particularly in regard to musculoskeletal features. This contributes to the challenge of phenotype-based clinical diagnoses. However, some hereditary connective tissue disorders have distinct cardiovascular manifestations that require early intervention and specific management. Molecular testing has increased the ability to categorize and diagnose distinct hereditary connective tissue disorders. A 42-yr-old female with a clinical diagnosis of Larsen syndrome from birth presented for genetic testing based on her recent diagnosis of premenopausal breast cancer. She had a past medical history of multiple carotid dissections. As she never had confirmatory molecular genetic testing for Larsen syndrome, whole-exome sequencing was utilized to assess both hereditary cancer predisposition syndromes and connective tissue disorders. A homozygous pathogenic variant in the FKBP14 gene was identified associated with FKBP14 kyphoscoliotic Ehlers-Danlos syndrome. We recommend that patients with a clinical diagnosis of Larsen syndrome undergo broad-based molecular sequencing for multiple hereditary connective tissue disorders. Molecular diagnosis is particularly crucial for all individuals who have a history of significant vascular events in the setting of a clinical diagnosis only. Early diagnosis of a hereditary connective tissue disorder with vascular features allows for screening and subsequent prevention of cardiovascular events.

Exome sequencing analysis on products of conception: a cohort study to evaluate clinical utility and genetic etiology for pregnancy loss.

PURPOSE: Pregnancy loss ranging from spontaneous abortion (SAB) to stillbirth can result from monogenic causes of Mendelian inheritance. This study evaluated the clinical application of exome sequencing (ES) in identifying the genetic etiology for pregnancy loss. METHODS: A cohort of 102 specimens from products of conception (POC) with normal karyotype and absence of pathogenic copy-number variants were selected for ES. Abnormality detection rate (ADR) and variants of diagnostic value correlated with SAB and stillbirth were evaluated. RESULTS: ES detected 6 pathogenic variants, 16 likely pathogenic variants, and 17 variants of uncertain significance favor pathogenic (VUSfp) from this cohort. The ADR for pathogenic and likely pathogenic variants was 22% and reached 35% with the inclusion of VUSfp. The ADRs of SAB and stillbirth were 36% and 33%, respectively. Affected genes included those associated with multisystem abnormalities, neurodevelopmental disorders, cardiac anomalies, skeletal dysplasia, metabolic disorders, and renal diseases. CONCLUSION: These results supported the clinical utility of ES for detecting monogenic etiology of pregnancy loss. The identification of disease-associated variants provided information for follow-up genetic counseling of recurrence risk and management of subsequent pregnancies. Discovery of novel variants could provide insight for underlying molecular mechanisms causing fetal death.

Primary Cortisol Deficiency and Growth Hormone Deficiency in a Neonate With Hypoglycemia: Coincidence or Consequence?

Cortisol and growth hormone (GH) deficiencies are causes of neonatal hypoglycemia. When they coexist, a pituitary disorder is suspected. We present an infant with hypoglycemia in whom an ACTH receptor defect was associated with transient GH deficiency. A full-term boy with consanguineous parents presented with hypoglycemia (serum glucose 18 mg/dL) at 4 hours of life with undetectable serum cortisol (<1 µg/dL). Examination showed diffuse hyperpigmentation with normal male genitalia. Patient developed hyperbilirubinemia and elevated transaminase levels. GH levels of 6.8 ng/mL and 7.48 ng/mL during episodes of hypoglycemia, peak of 9.2 ng/mL with glucagon stimulation, and undetectable IGF-1 suggested GH deficiency. Thyroid function, prolactin, and gonadotropins were normal. Baseline ACTH was elevated at 4868 pg/mL, whereas serum cortisol remained undetectable with ACTH stimulation. Hydrocortisone replacement resulted in normalization of blood glucose and cholestasis with decline in ACTH level. GH therapy was not initiated, given improvement in cholestasis and euglycemia. An ACTH receptor defect was confirmed with molecular genetic testing that revealed homozygosity for a known mutation of the melanocortin 2 receptor (MC2R) gene. At 12 weeks, a random GH level was 10 ng/mL. IGF-1 was 75 ng/mL and 101 ng/mL at 7 and 9 months, respectively. This report describes glucocorticoid deficiency from an MC2R mutation associated with GH deficiency. With glucocorticoid replacement, GH secretion normalized. Our findings are consistent with a previously stated hypothesis that physiologic glucocorticoid levels may be required for optimal GH secretion [1].

In-frame de novo mutation in BICD2 in two patients with muscular atrophy and arthrogryposis.

We describe two unrelated patients, a 12-yr-old female and a 6-yr-old male, with congenital contractures and severe congenital muscular atrophy. Exome and genome sequencing of the probands and their unaffected parents revealed that they have the same de novo deletion in BICD2 (c.1636_1638delAAT). The variant, which has never been reported, results in an in-frame 3-bp deletion and is predicted to cause loss of an evolutionarily conserved asparagine residue at position 546 in the protein. Missense mutations in BICD2 cause autosomal dominant spinal muscular atrophy, lower-extremity predominant 2 (SMALED2), a disease characterized by muscle weakness and arthrogryposis of early onset and slow progression. The p.Asn546del clusters with four pathogenic missense variants in a region that likely binds molecular motor KIF5A. Protein modeling suggests that removing the highly conserved asparagine residue alters BICD2 protein structure. Our findings support a broader phenotypic spectrum of BICD2 mutations that may include severe manifestations such as cerebral atrophy, seizures, dysmorphic facial features, and profound muscular atrophy.

LOXL1 expression in lens capsule tissue specimens from individuals with pseudoexfoliation syndrome and glaucoma.

PURPOSE: To study lysyl oxidase-like 1 (LOXL1) expression in freshly collected lens capsules from pseudoexfoliation syndrome (XFS), pseudoexfoliation glaucoma (XFG), and normal cataract control individuals. We also investigated the effects of four glaucoma drug medications on LOXL1 expression in primary human lens epithelial cell cultures to see if they could affect LOXL1 expression. METHODS: Lens capsules were collected at the time of cataract surgery. Controls were matched to age, sex, and ethnicity. Total RNA was isolated from individual lens capsule samples and real-time PCR was performed on each sample using primers flanking the sixth exon of the LOXL1 gene. Cell cultures were grown to confluence in four separate six-well plates at 37 °C in 5% CO2. Each plate was then treated with one of four different glaucoma drugs (brinzolamide 1%, brimonidine tartrate 0.1%, timolol maleate 0.5%, and latanoprost 0.005%) once daily for seven days (at both 1:1,000 and 1:100 concentrations relative to media). Controls were not treated with any drug but media was changed in the same manner. After one week of treatment, cells were harvested and total RNA isolated. Real-time PCR was performed on each group of cells. RESULTS: Seven XFS, seven XFG, and ten cataract control specimens were analyzed. LOXL1 expression was detected in the lens capsule specimens from each of the four groups. Significant expression differences were found between the control and XFG groups and XFS and XFG groups. No significant difference was observed between the control and XFS group. No significant decrease in LOXL1 expression was seen with drug incubation of the four medications (Brinzolamide, Timolol, Latanoprost, and Brimonidine) at the 1:1,000 drug:media concentrations versus controls. At 10-fold higher concentrations (1:100 drug:media), brinzolamide, timolol maleate, and latanoprost showed small increases in LOXL1 expression relative to controls. This effect was not observed with brimonidine tartrate. CONCLUSIONS: These results establish that LOXL1 expression is reduced in lens capsule specimens from XFG individuals but not XFS. The drug treatment incubation studies suggest that the change in LOXL1 expression observed in XFG is not attributable to glaucoma drug therapy. If a causative functional relationship can be validated, modification of LOXL1 expression in affected tissues may represent a novel treatment strategy for this disorder.