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UNASSIGNED: To perform molecular genetic analysis of a patient diagnosed with primary hypertrophic osteoarthropathy (PHO) with malnourishment, intussusception, and acro-osteolysis.
UNASSIGNED: At the age of 7 years, a boy born to a consanguineous couple was diagnosed with PHO attributed to delayed closure of the cranial suture, eczema, clubbing of fingers, and swelling of the knee and ankle. Clinical characteristics and follow-up data for 3 years were collected and analyzed. Trio whole-exome sequencing (WES) and copy number variant sequencing were used to screen for causative genetic variants. Candidate variants of the patient and his parents were confirmed by Sanger sequencing. When he was 7 years old, trio WES found that he had biallelic novel variants c.498 + 1G > A, inherited from his parents, in the HPGD gene. The patient was markedly malnourished. Ultrasonography and computed tomography showed intussusception with a gradual expansion of the duodenum, localized intestinal wall thickening, and acro-osteolysis. Cross-sectional blood tests showed that the patient had continuously decreased levels of serum 25-hydroxy vitamin D and serum ferritin at the age of 7and 10 years.
UNASSIGNED: PHO due to HPGD defects is rare in pediatric patients, and finding homozygous novel c.498 + 1G > A has expanded the spectrum of causative variants of HPGD and provided a clue for genotype-phenotype correlation analysis. Similar to mouse model results, human HPGD deficiency may also cause abnormal digestive tract development, and related secondary vitamin D deficiency and acro-osteolysis should be considered in HPGD-related PHO.

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BACKGROUND: Hajdu-Cheney syndrome (HCS) is a rare inherited skeletal disorder caused by pathogenic mutations in exon 34 of NOTCH2. Its highly variable phenotypes make early diagnosis challenging. In this paper, we report a case of early-onset HCS with severe phenotypic manifestations but delayed diagnosis.
METHODS: The patient was born to non-consanguineous, healthy parents of Chinese origin. She presented facial anomalies, micrognathia and skull malformations at birth, and was found hearing impairment, congenital heart disease and developmental delay during her first year of life. Her first visit to our center was at 1 year of age due to cardiovascular repair surgery for patent ductus arteriosus (PDA) and ventricular septal defect (VSD). Skull X-ray showed wormian bones. She returned at 7 years old after she developed progressive skeletal anomalies with fractures. She presented with multiple wormian bones, acro-osteolysis, severe osteoporosis, bowed fibulae and a renal cyst. Positive genetic test of a de novo heterozygous frameshift mutation in exon 34 of NOTCH2 (c.6426dupT) supported the clinical diagnosis of HCS.
CONCLUSIONS: This is the second reported HCS case caused by the mutation c.6426dupT in NOTCH2, but presenting much earlier and severer clinical expression. Physicians should be aware of variable phenotypes so that early diagnosis and management may be achieved.

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BACKGROUND: Mandibuloacral dysplasia type A (MADA) is a rare autosomal recessive disorder, characterized by growth retardation, skeletal abnormality with progressive osteolysis of the distal phalanges and clavicles, craniofacial anomalies with mandibular hypoplasia, lipodystrophy and mottled cutaneous pigmentation. Some patients may show progeroid features. MADA with partial lipodystrophy, more marked acral, can be caused by homozygous or compound heterozygous mutation in the gene encoding lamin A and lamin C (LMNA). MADA and Hutchinson-Gilford progeria syndrome are caused by the same gene and may represent a single disorder with varying degrees of severity. MAD patients characterized by generalized lipodystrophy (type B) affecting the face as well as extremities and severe progressive glomerulopathy present heterozygous compound mutations in the ZMPSTE24 gene.
UNASSIGNED: We described a rare pedigree from Southern China, among them all three children presented with phenotypes of MADA associated progeria. The two elder sisters had developed severe mandibular hypoplasia associated progeria since the age of 1 year. The eldest sister showed a progressive osteolysis. The youngest son of 10 months showed severer lesions than those of his sisters at the same age, and presented possible muscle damage, and his symptoms progressed gradually. Three genes mutations including LMNA, ZMPSTE24 and BANF1 were tested in the family. LMNA gene sequencing revealed a homozygous missense mutation, c.1579C > T, p.R527C for all three siblings, and heterozygous mutations for their parents, whereas no mutations of ZMPSTE24 and BANF1 genes was detected among them.
CONCLUSIONS: The same homozygous mutation of c.1579C > T of LMNA gene led to MADA associated progeria for the present family. The course of osteolysis for MADA is progressive.

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