Identification of a Novel Homozygous IHH Variant Causing Novel Acromesomelic Maroteaux-Type Skeletal Dysplasia in a Pakistani Family

M Hanif; B Ahmad; S Farman; S Hassan; A Hayat; N Bibi; U Kalsoom; B Khan

doi:10.2478/bjmg-2025-00024

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Identification of a Novel Homozygous IHH Variant Causing Novel Acromesomelic Maroteaux-Type Skeletal Dysplasia in a Pakistani Family

Balkan Journal of Medical Genetics

Volume 28 (2025): Issue 2 (December 2025)

By: M Hanif, B Ahmad, S Farman, S Hassan, A Hayat, N Bibi, U Kalsoom and B Khan

Open Access

|May 2026

Figures & Tables

(a) Pedigree of family exhibiting autosomal recessive pattern. (b) The father (III-7), of average height along with the affected males (IV-4, IV-1) who are short statured with normal trunk length and markedly shortened arms and legs. (c, d) Hands of affected males (IV-1 and IV-4) are short and broad. Clinodactyly is seen. Nails are dystrophic, with irregular curvature and thickening. (e, f) Clinical Photographs of feet of IV-1and IV-4 demonstrate broad, flat feet with disproportionately short and stubby toes. Toenails are dystrophic, with bilateral hyponychia of the great toes.

(a–d) Lateral and anteroposterior (AP) skull radiographs of affected individual IV-1 and IV-4 show generalized calvarial thickening with absence of frontal bossing and no evidence of macrocephaly. (e–h) Left and right upper limb radiograph of affected individuals (IV-1, IV-4) showing bilateral shortening of the radius and ulna, with cortical thickening and narrowed medullary canals, most pronounced in the distal radius. Features of true Madelung deformity, including volar-ulnar bowing of the distal radius, dorsal subluxation of the distal ulna and increased radial inclination are also observed. (i,j,k) Chest radiographs of individuals IV-1, IV-3 and IV-4 reveals normal rib and clavicular structure (l–n) Hand radiographs of all three affected siblings demonstrate severe brachydactyly. A V-shaped configuration of the proximal carpal row is also observed in the individual IV-3. (o–q) AP pelvic radiographs of the affected individuals (IV-1, IV-3 and IV-4) demonstrate bilateral coxa vara, and femoral bowing. (r–t) Lower limb radiographs of the individuals IV-1, IV-3 and IV-4 show shortened and broadened tibia and fibula with genu varum. Flared and irregular metaphyses of the distal femora and proximal tibiae, cortical thickening with narrowed medullary canals is noted. Multiple well-defined calcified loose bodies are seen in the left suprapatellar pouch and juxta-articular region in the affected individual IV-1. (u–v) Foot radiographs of the individuals IV-1, IV-4 depict short and broad tarsals, metatarsal, and phalangeal bones with bilateral fusion of the distal phalanges of the fifth toes. The distal metatarsal and proximal phalangeal epiphyses appear broad and squared. Fixed plantar flexion of the forefeet and equinus deformity at the ankle joints are also evident.

(a) Sanger electrograms of the variant (c.1018G>A; p. Val340Met) identified in an affected (upper panel), a carrier (middle panel) and a normal (lower panel) (b) Showing conservation of valine amino acid across several species. Secondary structure of (c)IHHWT and (d) IHHVal340Met. Structure validation through Ramachandran plot (e) IHHWT and (f) IHHVal340Met (g) and (h) represents ribbon form of wild type and mutant tertiary structures respectively. (i) Superimposition of mutant and wild type IHH auto processing domain.

(a) Ribbon representation of protein in grey colour with mutant residue in magenta colour. In close up view side chain of both wild type and mutant residues are shown in green and red colour respectively. (b) schematic structures of the original (left) and the mutant (right) amino acid. The backbone, which is the same for each amino acid, is coloured red. The side chain, unique for each amino acid, is coloured black. RMSF analysis (c, d) simulation trajectories and (e) C-α distance restraints analysis.

Pathogenicity of the identified variant (c_1018G>A; p_ Val340Met)

S. No	Tool used	Prediction
1	Mutation Taster	Disease causing
2	SIFT	Damaging
3	Provean	Neutral
4	PolyPhen-2	Damaging
5	DANN	Disease causing (0.9986)
6	FATHMM-MKL	Damaging (Coding score 0.9894)
7	FATHMM	Damaging

Phenotypic comparison of the patients reported in the present family with AMDM, ACFD, AMD2A, AMD2B and AMD2C

Characteristics	Current Study			AMD1/Maroteaux	ACFD	AMD2A / Grebe (GDF5)	AMD2B / Du Pan (GDF5)	AMD2C (GDF5)
Characteristics	IV-1	IV-3	IV-4	AMD1/Maroteaux	ACFD	AMD2A / Grebe (GDF5)	AMD2B / Du Pan (GDF5)	AMD2C (GDF5)
Phenotypic Features
Age (years)	26	28	22	NA	NA	NA	NA	NA
Height (cm ± SD)	116.84 cm (−9.6 SD)	99.06cm (−9.7 SD)	121.92cm (−10.4 SD)	<125 cm (−6 to −10 SD)	84, 102 cm (−2.3 to −9.6 SD)	~100 cm (severe)	Mild–moderate short stature	Severe short stature
Weight (kg)	38.5,	32.0	,38	Low	20–30	Low	Low	Low
Head Circumference (cm ± SD)	54.61	50.8	53.84	Macrocephaly	50.8–54.6	Normal	Normal	Normal
Acromesomelic Limb Shortening	✓	✓	✓	✓	✓	✓ (Severe Distal)	✓	✓
Head size	Near normal	Near normal	Near normal	Normal	Large	Normal	Normal	Normal
Intelligence	Normal	Normal	Normal	Normal	Normal	Normal	Normal	Normal
Brachydactyly	✓	✓	✓	✓	✓	✓ (Severe)	✓ (complex)	✓
Clinodactyly	✓	✓	✓	✓	✓	✓	✓	✓
Hyponychia	✓	✓	✓	✕	✕	✕	✓	✕
Loose redundant skin	✕	✕	✕	✓	✕	✓	✓	✓
Joint laxity	✕	✕	✕	✓	✕	✕	✕	✓
Feet deformity	Equinus deformity/Metatarsus Adductus	Equinus deformity/Metatarsus Adductus	Equinus deformity/Metatarsus Adductus	Large halluces	Pes planus	Valgus foot deformity	Talipes equinovalgus	Short feet
Radiological Features
Radial bowing & angulation	Severe (Madelung-like)	Severe (Madelung-like)	Severe (Madelung-like)	✓	Mild due to coning	✕	✕	✕
Dislocated radial head	✓	✓	✓	Rare	Rare	✓	Occasional	occasional
Subluxation of ulnocarpal joint	✓	✓	✓	✕	✕	✓	✓	✓
Retarded/dislocated Carpal bone age	Marked Delay	Marked Delay	Marked Delay	Marked Delay	Moderate Delay	Extreme Delay/Fused	Mild Delay/Fused (Rudimentary)	Mild Delay/Fused (Rudimentary)
Suprapatellar Loose Bodies	✓	✕	✕	✕	✕	✕	✕	✕
Fusion of phalanges	Synostosis	Synostosis	Synostosis	✕	Synostosis	Symphalangism	Symphalangism	✕
Metacarpals	Short	Short	Short	Short	Teardrop	Rudimentary or absent metacarpals	Tear drop	Cuboidal/Extremely short
Short phalanges	Proximal phalanges	Proximal phalanges	Proximal phalanges	Middle and proximal phalanges	Middle and Distal	Rudimentary (distal present only)	Middle and proximal	Middle and proximal
Thorax	Normal	Normal	Normal	Normal	Narrow	Normal	Normal	Normal
Vertebral changes	✕	✕	✕	(kyphosis)	(lumbar lordosis)	✕	✕	✕
Chest	Normal	Normal	Normal	Superiorly curved clavicles	Pectus deformities	Normal	Normal	Normal
Acetabulum	Normal	Normal	Normal	Dysplastic	Dysplastic	Dysplastic	Dysplastic	Dysplastic
Iliac Wings	Normal	Normal	Normal	Squared	Short	Hypoplastic	small	small
Coxa valga / vara	Vara	Vara	Vara	Valga	Vara	Dislocated	Valga	Valga
Cortical Thickness	Increased	Increased	Increased	Normal	Normal	Normal	Normal	Normal
Medullary canals	Narrow	Narrow	Narrow	Normal	Normal	Normal	Normal	Normal
Short tibia/fibula	✓	✓	✓	✓	✓	✓ (Severely shortened)	✓ (fibula absent/hypoplastic)	✓
Metaphyseal Shape	Flared/Irregular	Flared/Irregular	Flared/Irregular	Severely Flared	V shaped	Rudimentary	Normal	Normal
Cone Shaped Epiphysis	✕	✕	✕	✕	✓	✕	✕	✕
Short femoral neck/shaft	✓	✓	✓	✓	✓	✓	✓	✓
Distal femur	Hyper Plastic	Hyper Plastic	Hyper Plastic	Broad	Normal	Hypoplastic	Normal to broad	Normal
GenuValgum/Varum	Varum	Varum	Varum	✕	Varum	Valgum	Valgum	Valgum
Autosomal Recessive Inheritance	✓	✓	✓	✓	✓	✓	✓	✓
Gene mutated	IHH	IHH	IHH	NPR2	IHH	GDF5	GDF5	GDF5

The sequence variant was classified as likely pathogenic based on ACMG criteria (Richards et al_ 2015) [30]

Gene	IHH
Variant	c.1018G>A, p. Val340Met)
ACMG criteria pathogenic variant
Strong
PS1 - same AA as established pathogenic variant
PS2 - denovo
PS3 - invitro assay
PS4 - increase prevalence of the variant
Moderate
PM1 - Mutational hotspot and/or critical and well-established functional domain
PM3 - cis/trans with pathogenic variant
PM4 - Protein length change
PM5 - same aa position, different change
PM6 - assumed denovo
Supporting
PM2 - absent from controls	✓
PP1 - cosegregation	✓
PP2 - low rate of benign missense variation	✓
PP3 - computaional evidence support	✓
PP4 - patient phenotypes highly specific	✓
PP5 - reputable resource reports as pathogenic

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DOI: https://doi.org/10.2478/bjmg-2025-00024 | Journal eISSN: 2199-5761

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Language: English

Page range: 29 - 40

Published on: May 14, 2026

Published by: Macedonian Academy of Sciences and Arts

In partnership with: Paradigm Publishing Services

Publication frequency: 2 issues per year

Keywords:

Acromesomelic Maroteaux type,

autosomal recessive,

homozygous missense variant,

IHH gene

Related subjects:

Medicine,

Basic medical science,

Basic medical science, other

© 2026 M Hanif, B Ahmad, S Farman, S Hassan, A Hayat, N Bibi, U Kalsoom, B Khan, published by Macedonian Academy of Sciences and Arts
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Volume 28 (2025): Issue 2 (December 2025)

Identification of a Novel Homozygous IHH Variant Causing Novel Acromesomelic Maroteaux-Type Skeletal Dysplasia in a Pakistani Family

Figures & Tables

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Pathogenicity of the identified variant (c_1018G>A; p_ Val340Met)

Phenotypic comparison of the patients reported in the present family with AMDM, ACFD, AMD2A, AMD2B and AMD2C

The sequence variant was classified as likely pathogenic based on ACMG criteria (Richards et al_ 2015) [30]

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