The synthesis of PAPS (3-phosphoadenosine 5-phosphosulfate) - a sulfate donor - is catalyzed by two isoenzymes (PAPS synthase1 and PAPS synthase 2). PAPSS1 is ubiquitously expressed in human tissues, including cartilage. PAPSS2 shows a restricted expression pattern and is the major isoform involved in cartilage growth. PAPSS2 is responsible from the sulfation of dehydroepiandrosterone (DHEA) which is an androgen precursor. Impaired sulfation of DHEA leads to increase in the levels of active androgens and clinical findings of hyperandrogenism occurs. Homozygous mutations in the PAPSS2 gene lead to impaired sulfation of proteoglycans and cause spondyloepimetaphyseal dysplasia (SEMD) Pakistani type which is characterized by short stature, short bowed legs, platyspondyly, narrow intervertebral spaces, short femoral neck, irregular metaphyses, and epiphyses. The aim of this study was to describe the molecular, clinical, and endocrinological features of patients diagnosed with SEMD Pakistani type.
Seven patients from three families were evaluated. 5 patients from the first family (16y/M-33y/F-38y/F-34y/M-14y/M) had short stature (-5 SDS/-6 SDS/-6 SDS/-3.7 SDS/-2 SDS, respectively). A 33-year-old female patient had oligomenorrhea, hirsutism, and mildly elevated testosterone level after puberty and a 38-year-old female patient had infertility for 5 years. A 7-year-old girl from the second family suffered from back pain and short stature (-2SDS) and a 15-year-old girl from the third family had scoliosis and short stature (-5.45SDS).
All cases were clinically and radiologically compatible with SEMD Pakistani type. Plasma level of DHEAS was low in all patients. Homozygous c.1000C>T mutation was found in patients from the first and third families and compound heterozygote novel pathogenic c.639+1G>T and c.1000C>T mutations were found in a patient from the second family.
In conclusion, endocrinologic problems can be seen in patients with SEMD Pakistani type and patients should be monitored for these disorders.