Mucolipidosis type III (ML III, MIM 252605), known as pseudo-Hurler polydystrophy, is an autosomal recessive disease caused by deficiency of UDP-N-acetylglucosamine 1-phosphotransferase [
4]. This enzyme is requested during the labeling of the acid hydrolases (AH) by the mannose-6-phosphate (M6P) in the cis Golgi cisterns [
5]. Only tagged AH are binded to M6P-receptors in the trans-Golgi and then delivered to the lysosome.The lack of M6P result in impaired targeting of hydrolases to lysosome, leading to their excessive release into the extracellular compartment [
6]. As a consequence, cells accumulate undigested macromolecules in their endosomes/lysosomes [
7]. Clinically, ML III is milder than other forms of mucolipidosis; this begins often from 3 years with slow coarsening of the facial features, growth deficiency, progressive joint stiffness, claw hand deformity, gait impairment with hip disease, scoliosis, dysostosis multiplex, normal intelligence or mild intellectual disability [
8,
9]. Laboratory diagnosis is readily made by demonstrating increased lysosomal enzyme levels in serum, and reduced levels in extracts of cultured fibroblasts [
10]. Clinical presentation of the ML III is heterogeneous [
11], and constitutes a challenge area with different diagnosis. Thereby, ML III α/β and ML III γ are almost indiscernible Clinically [
12]. Rheumatologic disorders, such as juvenile idiopathic rheumatoid arthritis, progressive pseudorheumatoid arthritis of childhood and scleroderma, are usually suspected in individuals with ML III [
13,
14]. Our proband exhibited notably dermatological and rheumatological manifestations mimicking scleroderma. He had retracted, hard, tight and dry skin, Raynaud’s syndrome, hyper- and hypopigmentation areas. However, these alterations were seldom noted in individuals with ML III [
15]. Skin biopsy in these patients revealed increased cytoplasmic lysosomal granules or inclusions in lymphocytes and fibroblasts in various tissues. This histopathologic finding is known as I-cell phenotype [
16], and was not obvious in our family. In addition, our patient had rheumatological manifestations mainly joint stiffness, elbows flexum, tendon retraction (wrist, MCP and PIP joints), limitation of hip abduction/rotation, limping gait, genu valgum, and kyphosis. Other finding were bilateral osteonecrosis of the femur, bone demineralization and joint space narrowing over the hand. Joint manifestations have been described in 46% to 97% of patients with scleroderma [
17], predominantly at the hand joints, in particular the MCP and PIP joints [
18,
19]. Radiological signs were mostly joint space narrowing, bone demineralisation, acro-osteolysis, flexion contracture, and calcinosis [
18]. However, bone necrosis has been rarely associated with scleroderma [
20]; This was considered as a common complication of steroid therapy, and microvascular involvement as well [
21,
22].
In this paper, due to clinical heterogeneous presentation of the disorder as well as recurrence in sibling, we opted for the WES which allowed to maintain the right diagnosis and exclude other differential ones. By that, two compound heterozygous mutations causing ML III gamma in Moroccan family were identified in the
GNPTG gene, including a maternally inherited nonsense mutation c.196C>T (p.Arg66Ter), and a paternally inherited deletion mutation c.635_636delTT (p.Phe213Ter), in all three patients. The first variant is a single nucleotide substitution located in exon 4, described once as a pathogenic mutation that is predicted to severely damage the protein product [
23]. The second mutation is a small deletion c.635_636delTT (p.Phe213Ter) located in exon 9, this variant was reported in heterozygous state in healthy people, but never seen in affected individuals, making it a new pathogenic mutation related to mucolipidosis. Based on UCSC server (Fig.
3), these mutations lies within a conserved domain. To the best of our knowledge, 24 different mutations in the
GNPTG gene have been reported, including six missense/nonsense mutations, seven small deletions, four small insertions, two gross deletions and five splice site mutations [
http://www.hgmd.cf.ac.uk/ac/gene.php?gene=GNPTG]. However, no
GNPTG mutations have been reported in the Moroccan population yet.