Hypophosphatasia and Microcephalic Osteodysplastic Primordial Dwarfism Type II: Diagnosing Patients with Minor Symptoms

Hypophosphatasia (HPP) and Microcephalic Osteodysplastic Primordial Dwarfism type II (MOPD II) are rare inherited diseases which arise from the ALPL gene and PCNT gene respectively. HPP has nonspecific alkaline phosphatase (TNSALP) deficiency which causes the manifestations of skeletal deformities, fractures, nephrocalcinosis, seizures, respiratory failure and poor dentition. While in MOPD typically presents with bone, vascular and hematological abnormalities. Both of these diseases have a variety of symptoms which can vary in severity which can make the diagnosis difficult but important to avoid future complications.

Case Description:

A 41-year-old woman was referred to endocrinology for evaluation of low alkaline phosphatase (ALP) level by her primary care physician. The patient’s abnormal laboratory results were found during her yearly analysis. ALP was below normal range at 24 IU/L. She related that both her sisters have a history of low ALP. The patient complains of bilateral hip pain and brittle teeth for which she has required multiple root canals throughout the years. She related that her mother had similar dental issues. Further laboratory analysis showed persistent low ALP with values of 24 IU/L and 27 IU/L 3 months apart. The patient underwent genetic testing that resulted in positive ALPL and PCNT genes. The patient was offered enzyme replacement therapy with Asfotase Alfa for her HPP but declined owing to minimal symptoms. The patient will continue to be monitored to avoid further complications.

Discussion:

Hypophosphatasia can either be an autosomal recessive or autosomal dominant. The exact prevalence is not well known but the rarity of the disease causes many physicians to overlook or not consider the disease. TNSALP deficiency causes an accumulation of substrates and inability to convert these into hydroxyapatite or neurotransmitters such as GABA and dopamine. This can lead to pathological fractures and intractable seizures.

MOPDII has the PCNT gene affected which oversees the pericentrin protein. The disease has classical features of pre and postnatal growth retardation, microcephaly, skeletal dysplasia and vascular abnormalities. Patients with this disease have dental issues such as enamel hypoplasia with absent roots to the teeth. This disease can also present with Moyamoya disease and aneurysms, which can lead to further complications and death.

This case report demonstrates the variability of the HPP and MODP II. The few symptoms of both shows how they can be overlooked so effortlessly. The patient only demonstrated poor dentition and joint pain which could be caused by a vast array of other diseases. The genetic testing will help the physician avoid prescribing medication or vitamins that could worsen or bring arise to new symptoms. An example of this is prescribing high dose vitamin D, calcium and bisphosphonates owing to the increase in serum calcium levels. In conclusion, HPP and MOPD II are genetic diseases which if only minor symptoms are present can be easily overlooked, misdiagnosed and mistreated.