DNAJC12 deficiency (OMIM# 617384) is a new cause of hyperphenylalaninemia (HPA). The deficiency of the co-chaperone protein DNAJC12 was identified in 2017. To date, only 43 patients have been ...reported. Here, we report four patients from a single family with DNAJC12 deficiency while being followed up with a diagnosis of HPA.
Two of the patients, who were cousins, were diagnosed with HPA by newborn screening. And the other two patients were siblings of these patients. Neurological examinations were normal except for one patient with mild learning disability. A c.158-2A>T p.(?) biallelic pathogenic variant was detected in intron 2 of the
gene. In the 24 h tetrahydrobiopterin (BH4) challenge test, there was a significant decrease in phenylalanine levels, especially at the 16th hour. Three patients had decreased homovalinic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) in cerebrospinal fluid (CSF), while only one had decreased 5HIAA. In treatment, sapropterin, levodopa/carbidopa and 5-OH tryptophan were started.
We propose that it will be beneficial to evaluate the patients who have unexplained hyperphenylalaninemia for DNAJC12 deficiency. Patients with early diagnosis of neurotransmitter deficiency may be given a chance to be treated before clinical symptoms begin.
The “blepharophimosis‐mental retardation” syndromes (BMRS) consist of a group of clinically and genetically heterogeneous congenital malformation syndromes, where short palpebral fissures and ...intellectual disability associate with a distinct set of other morphological features. Kaufman oculocerebrofacial syndrome represents a rare and recently reevaluated entity within the BMR syndromes and is caused by biallelic mutations of UBE3B. Affected individuals typically show microcephaly, impaired somatic growth, gastrointestinal and genitourinary problems, ectodermal anomalies and a characteristic face with short, upslanted palpebral fissures, depressed nasal bridge. and anteverted nares. Here we present four patients with five novel UBE3B mutations and propose the inclusion of clinical features to the characteristics of Kaufman oculocerebrofacial syndrome, including prominence of the cheeks and limb anomalies.
Transient infantile hypertriglyceridemia (HTGTI) is caused by mutations in the glycerol-3-phosphate dehydrogenase 1 (
) gene. HTGTI is characterized by hypertriglyceridemia, hepatomegaly, hepatic ...steatosis and fibrosis in infancy. Here, we reported first Turkish HTGTI patient with a novel mutation of
, having hypertriglyceridemia, hepatomegaly, growth retardation and hepatic steatosis. He is the first case who needs transfusion until 6th month in GPD1.
A 2-month-27-day-old boy, who had growth retardation, hepatomegaly and anemia suffered to our hospital with vomiting. Triglyceride level was 1603 mg/dL (n<150). Liver transaminases were elevated and hepatic steatosis was developed. He needed transfusion with erythrocyte suspension until 6th month. Etiology could not be elucidated by clinical and biochemical parameters. A novel homozygous c.936_940del (p.His312GlnfsTer24) variant was detected in the
gene by Clinical Exome Analysis.
GPD1 deficiency should be investigated in the presence of unexplained hypertriglyceridemia and hepatic steatosis in children especially in infants.
Objective
Blomstrand osteochondrodysplasia (BOCD, MIM #215045) is an ultrarare lethal skeletal dysplasia (LSD) perinatally, characterized by extremely advanced bone maturation, generalized ...osteosclerosis, and severe tetramicromelia caused by biallelic loss‐of‐function mutations in the parathyroid hormone receptor‐1 gene (PTHR1). We aim to describe prenatal ultrasonographic features in a retrospective fetal case series of BOCD and emphasize the importance of multidisciplinary antenatal evaluation of LSDs to improve the differential diagnosis.
Method
Prenatal ultrasound findings of five fetal cases diagnosed with BOCD between 2000 and 2019 in the Prenatal Diagnosis Unit and Medical Genetics were reviewed, along with postmortem examination results and confirmatory molecular results.
Results
All fetuses presented with severe sonographic findings of LSDs comprising tetramicromelia, thoracic hypoplasia, and retro‐micrognathia. Marked cervical hyperextension was present in three fetuses. Flared metaphyses were prenatally identified in only one fetus. X‐rays of four fetuses evaluated postmortem showed advanced bone maturation, generalized osteosclerosis, and dumbbell‐like appearance of long bones due to metaphyseal enlargement.
Conclusion
The presence of retro‐micrognathia along with a protruding tongue and severe metaphyseal flaring can suggest a diagnosis of BOCD, when prenatal ultrasound findings are indicative for LSD. The diagnosis can be ascertained through postmortem clinical and radiological evaluation and/or molecular testing.
Key points
What's already known about this topic?
Postmortem radiologic diagnosis of Blomstrand osteochondrodysplasia (BOCD) has been well characterized. However, no specific antenatal ultrasound finding has been implemented in the diagnosis of this ultrarare skeletal dysplasia, except for severe tetramicromelia.
What does this study add?
It's emphasized that severe retro‐micrognathia may be a remarkable feature, in addition to previously well‐documented prenatal findings in BOCD. Meticulous prenatal ultrasound evaluation is required for the detection of flaring of metaphyses. Other ultrasound findings are proptosis, cervical hyperextension, and kyphoscoliosis.
Crisponi/cold‐induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by episodic hyperthermia, arthrogryposis, impaired feeding ability, and respiratory distress. ...The classic CS/CISS is mainly associated with CRLF1 and, rarely, CLCF1. PERCHING syndrome, previously known as CS/CISS type‐3 associated with biallelic pathogenic variants in KLHL7, is notable for its few overlapping manifestations. This study presents genotype–phenotype relationships in CS/CISS‐like spectrum associated with CRLF1 and KLHL7. Clinical findings of 19 patients from 14 families and four patients from three families were found in association with six different CRLF1 and three different KLHL7 variants, respectively. c.167T>C and c.713delC of the CRLF1 gene and the c.642G>C of the KLHL7 were novel. The c.708_709delCCinsT allele of CRLF1 was identified in 10 families from the Mardin province of Turkey, underlining that an ancestral haplotype has become widespread. CRLF1‐associated phenotypes revealed novel manifestations such as prenatal oligohydramnios, benign external hydrocephalus, previously unreported dysmorphic features emerging with advancing age, severe palmoplantar keratoderma and facial erythema, hypopigmented macules and streaks, and recurrent cardiac arrests. KLHL7 variants presented with glabellar nevus flammeus, blepharophimosis, microcephaly, thin corpus callosum, and cleft palate. Abnormalities of sweating, observed in one patient reported herein, is known to be very rare among KLHL7‐related phenotypes.
Postaxial polydactyly (PAP) is a frequent limb malformation consisting in the duplication of the fifth digit of the hand or foot. Morphologically, this condition is divided into type A and B, with ...PAP‐B corresponding to a more rudimentary extra‐digit. Recently, biallelic truncating variants in the transcription factor GLI1 were reported to be associated with a recessive disorder, which in addition to PAP‐A, may include syndromic features. Moreover, two heterozygous subjects carrying only one inactive copy of GLI1 were also identified with PAP. Herein, we aimed to determine the level of involvement of GLI1 in isolated PAP, a condition previously established to be autosomal dominantly inherited with incomplete penetrance. We analyzed the coding region of GLI1 in 95 independent probands with nonsyndromic PAP and found 11.57% of these subjects with single heterozygous pathogenic variants in this gene. The detected variants lead to premature termination codons or result in amino acid changes in the DNA‐binding domain of GLI1 that diminish its transactivation activity. Family segregation analysis of these variants was consistent with dominant inheritance with incomplete penetrance. We conclude that heterozygous changes in GLI1 underlie a significant proportion of sporadic or familial cases of isolated PAP‐A/B.
