Skeletal dysplasia

Gene: HSPA9

Green List (high evidence)

Comment on list classification: Skeletal dysplasia is a major feature of EVEN-PLUS syndrome, caused by biallelic variants in HSPA9. There are at least 7 unrelated EVEN-PLUS families reported in literature, with characteristic skeletal features: hypoplastic nasal bones, dysplastic femoral heads, bifid distal femurs, dysplastic epiphyses, delayed ossification, and short stature. Hence, this gene should be promoted to Green at the next update.

Created: 2 Sep 2026, 12:12 p.m. | Last Modified: 2 Sep 2026, 12:12 p.m.

Panel Version: 10.7

PMID: 26598328 Royer-Bertrand et al., 2015
Described the identification of biallelic variants in HSPA9 in three patients (two of which are siblings), with EVEN-PLUS syndrome.
Patient 1, Korean female, was found to be heterozygous for HSPA9 variants c.383A > G (p.Y128C) and c.882_883delAG (p.V296*). Patients 2 and 3 (sibs from Chile) were found to be homozygous for variant c.376C > T (p.R126W). Method: exome seq. Common features of the patients: hypoplastic nose, microtia / absent external ears, anal atresia in 2/3 patients.
P1 skeletal features: radiographs showed lateral vertebral clefts, dysplasia of the proximal femurs and acetabula, “bifid” distal femurs and marked epiphyseal dysplasia at her knees.
P2 skeletal features: underossified pubic bones; bilateral dysplasia of the femoral heads at birth resulting in hip dislocation at age 5 yrs; and a “bifid” appearance of the distal femur with epiphyseal delay at birth, with dysplastic epiphyses that are “socketed” in the bifid femur at age 5 yrs; and small, laterally dislocated patellae.

DOI:10.4172/1747-0862.1000350 Nagrani et al., 2018
Report of a 7-yo Indonesian female patient with Even-plus syndrome. She presented with abnormal posture and gait, midface hypoplasia, microtia, high-arched palate, leg length discrepancy (due to tight hamstring), short neck, kyphosis, scoliosis, and dislocated left patella. Bone survey revealed metaphyseal dysplasia and multiple vertebral clefts. Lower motor neuron or muscle involvement was excluded by EMG. She was comp het for HSPA9 variants c.446A>T, p.Asn149Ile and c.1687A>T, p.Lys563Ter.

PMID: 32869452 Younger et al., 2020
WES identified comp het HSPA9 variants c.818 T > G (p.L273X) and c.955C > T (p.L319F) in a male proband with EVEN-PLUS syndrome. Unique additional features of this patient: agenesis of the septum pellucidum, a short chest and sternum, 13 pairs of ribs, a single hemivertebra, laterally displaced nipples, hydronephrosis, unilateral cryptorchidism, unilateral single palmar crease, bilateral clubfoot, and hypotonia.

PMID: 35779070 Pacio-Miguez et al., 2022
Reported two families.
F1 - Exome seq of Spanish female proband identified comp het HSPA9 variants c.371T>C, p.Ile124Thr & c.376C>T, p.Arg126Trp. Variants also confirmed ini trans in affected brother by Sanger seq, and het in parents. Clinical features: imperforate anus, bilateral microtia, midface hypoplasia, 5th finger clinodactyly, as well as skeletal dysplasia features: dysplastic femoral head, bifid femur, dysplastic epiphyses, delayed ossification.
F2 - exome seq identified c.1085C>T, p.Thr362Ile in a homozygous state in 2 affected sisters (het in healthy parents).

PMID: 36094340 Watanabe et al., 2023
Case report of a Japanese male child with syndromic CSA. He had congenital heart disease (ventricular septal and atrial septal defects), hypospadias, developmental delay, posteriorly rotated auricles, and dental abnormalities. One day after birth, he was found to have anemia (hemoglobin, 6.7 g/dl). Comp het HSPA9 variants detected: c.1639delA, (p.Leu553*) and a SNP c.1933C>T, rs10117T, (p.Leu645=). His father had the same variants, but was not anemic. The mRNA and protein expression levels differed between the father and son. Parental exome seq and WGS of the mother did not reveal any other candidates.

PMID: 36052765 Li et al., 2022
Reported 2 Chinese sibs, male and female, with EVEN-PLUS. Proband had developmental delay since infancy, abnormal posture and gait for 12 years and 6 months, and intermittent seizures for more than 5 years. A radiological skeletal survey showed hypoplastic nasal bones; severe kyphosis and no vertebral clefting were identified. Femoral heads were flattened. Distal femoral epiphyses were dysplastic, with hypoplastic lateral condyle and deep intercondylar notches resembling bifid femora.
Sources: Literature

Created: 2 Sep 2026, 10:56 a.m. | Last Modified: 2 Sep 2026, 2:23 p.m.

Panel Version: 10.8

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Even-plus syndrome, OMIM:616854; even-plus syndrome, MONDO:0014801; epiphysial-vertebral-ear dysplasia-nose-plus associated findings syndrome

Publications

• 26598328
• DOI:10.4172/1747-0862.1000350
• 32869452
• 35779070
• 36094340
• 36052765