PYKNODYSOSTOSIS (OSTEOPETROSIS ACRO-OSTEOLYTICA)

Abstract

Objective:

To present a case of pyknodysostosis (PKND), a rare genetic cause of skeletal dysplasia that often goes undiagnosed even in patients with classic features.

Methods:

We report a case of PKND that went undiagnosed over many years despite classic features. We performed physical examination, imaging studies, and genetic testing on the patient.

Results:

A 21-year-old female presented to endocrinology to establish care. On evaluation, she was noted to have disproportionate short stature and a past medical history notable for bilateral blindness due to optic atrophy secondary to bone enlargement and thickening of the optic nerve canal before age 7 years. She also had a history of foot fractures occurring with ambulation. Her family history was significant for consanguineous parents and relatives with similar clinical features. Physical examination revealed a short, 128-cm tall female with open anterior and mastoid fontanels, mild frontal bossing and micrognathia, evidence of double rows of teeth, and digits of varied length in both hands and feet. Plain radiographs demonstrated diffuse sclerosis and marked cortical thickening of the pelvis, femurs, metacarpals, proximal phalanges, and metatarsals as well as decreased phalangeal length and acro-osteolysis of the hands and feet. Dual energy X-ray absorptiometry demonstrated increased bone mineral density (z scores +2.5 lumbar spine, +3.7 femoral neck, +4.5 total hip). Genetic testing revealed a exon 5-homozygous mutation in the cathepsin K (CTSK) gene consistent with PKND.

Conclusion:

Patients with PKND come to medical attention for a variety of reasons but often go undiagnosed even when presenting with classic features due to the rarity of the condition and the overlap with other skeletal dysplasias.

INTRODUCTION

Pyknodysostosis (PKND) is a rare disorder first described in 1962. Clinical features include midfacial hypoplasia, prominent cheeks, high nasal bridge, beaked nose, frontal bossing, open fontanel, dental anomalies, and shortened fingers with spoon-shaped nails (acro-osteolysis) resulting from resorption of the distal phalanges. Premature fusion of the fibrous sutures of the skull (craniostenosis) results in the abnormal cranial and facial features. Other clinical features include increased intracranial pressure, visual impairment, disproportionate short stature, and osteosclerosis with bone fragility.

PKND is caused by mutations in the gene for cathepsin K (CTSK), a cysteine protease that is highly expressed in osteoclasts (1) and results in decreased bone resorption (2) (Fig. 1). The disease is inherited in an autosomal recessive fashion with a prevalence between 1 to 3 per million (3). In clinical practice, PKND represents a diagnostic challenge not only because of the low prevalence of the disease but also the clinical heterogeneity of presentation (4).

Fig. 1.

Cathepsin K is a cysteine protease expressed predominantly in osteoclasts, and its deficiency or dysfunction causes pyknodysostosis.

We report a case of PKND exhibiting common features of the disease that went undiagnosed despite a positive family history and involvement of multiple specialists to manage the complications of her disease.

CASE REPORT

A 21-year-old female with history of osteopetrosis presented to endocrinology clinic to establish care after recently arriving in the United States from the Middle East. Her past medical history was notable for disproportionate short stature and bilateral blindness (no light perception). She suffered optic atrophy secondary to bone enlargement and thickening of the optic nerve canal of the right eye before age 2 years. She experienced the same complication in her left eye before age 7 years. Later in childhood she suffered several fragility fractures of both lower extremities with ambulation. Investigation led to the diagnosis of osteopetrosis.

Additional history revealed a prenatal course complicated by intrauterine growth restriction and size small for gestational age at birth. She reported a complicated dental history which included multiple tooth extractions for retained deciduous teeth and trismus. Menarche occurred at age 11 with regular menses. She denied history of intellectual disability and currently attends law school. She was not taking any medication.

Family history was significant for consanguineous parents who were double first cousins and at least 1 paternal cousin and 2 more distant maternal relatives with similar clinical features. A family pedigree is presented in Figure 2. Her father, mother, and 15-year-old brother are healthy. The patient underwent genetic testing 3 years prior and reported the results were normal.

Fig. 2.

Family pedigree was significant for consanguineous parents who were double first cousins and at least 1 paternal cousin and 2 more distant maternal relatives with similar clinical features.

On physical examination, she had disproportionate short stature with a height of 126.7 cm (<third percentile), weight of 51.7 kg (10 to 25th percentile), body mass index of 31.6 kg/m², and head circumference of 54 cm (reference range is 25 to 50 cm). The remainder of the examination was notable for open anterior and mastoid fontanels, mild frontal bossing, micrognathia, absent vision bilaterally, aquiline nose, double rows of teeth, inability to open the mouth fully (Fig. 3 A and B), brachydactyly of all fingers and toes, Tanner stage 5 breasts, and no neurological deficit or birthmarks.

Fig. 3.

Image showing aquiline nose, double rows of teeth, and inability to open the mouth fully.

Laboratory results showed normal complete blood count, complete metabolic panel, and prolactin. Bone turnover markers were assessed with thyroid-stimulating hormone at 5.3 μIU/mL (reference range is 0.3 to 4.2 μIU/mL), thyroid peroxidase antibody of 459 IU/mL (reference range is 0 to 34 IU/mL), thyroglobulin antibody of 8.8 IU/mL (reference range is 0 to 0.9 IU/mL), 25-hydroxyvitamin D of 12.9 ng/mL (reference range is 29 to 100 ng/mL), and parathyroid hormone of 65 pg/mL (reference range is 15 to 65 pg/mL). Plain radiographs demonstrated open fontanels (Fig. 4 A) as well as diffuse sclerosis and marked cortical thickening especially of the pelvis, femurs (Fig. 4 B), metacarpals, metatarsals, and proximal phalanges. Decreased phalangeal length and acro-osteolysis of the hands (Fig. 4 C) and feet were also noted. Bone densitometry was normal (z scores were +2.5 lumbar spine, +3.7 femoral neck, +4.5 total hip).

Fig. 4.

Plain radiographs demonstrating open fontanels (A), diffuse sclerosis, and marked cortical thickening of the pelvis and femurs (B). There is also decreased phalangeal length and acro-osteolysis of the hands (C).

Genetic testing was performed by Connective Tissue Gene Tests (Allentown, PA). All other laboratory tests and dual energy X-ray absorptiometry were performed at Walter Reed Military Medical Center. Genetic testing revealed a CTSK exon 5-homozygous mutation (c539G>A). This result together with the radiographic and physical findings was consistent with a diagnosis of PKND. This variant had not been previously reported.

DISCUSSION

PKND is most commonly diagnosed in childhood, when clinical investigation of disproportionate short stature and characteristic facial features, teeth abnormalities, and bony abnormalities often prompt specialty referral to a pediatric geneticist. Investigation of a fragility fracture with plain radiographs often demonstrates findings consistent with a sclerosing bone disorder and is another common presentation leading to diagnosis (4,5).

While PKND was first described in 1962 (6,7), it remains an exceedingly rare diagnosis until recently (3,8,9). Differential diagnoses include fluorosis, malignancy, myelosclerosis, other forms of osteopetrosis, Pagets disease, and acromegaly. Our patient did not have any clinical features to suggest any of these disorders. She came to the attention of multiple specialists over many years unable to make the correct diagnosis until age 21 when repeat genetic test confirmed a novel mutation.

Three hallmark features of PKND are disproportional short stature, osteosclerosis, and acro-osteolysis. While it is difficult to define a classic presentation of PKND given the heterogeneity of clinical features, recent case series have shed light on the more common features of the disease which can inform clinical decision making and diagnostic workup (8,9).

Disproportionate short stature is often the first indication of PKND that comes to the attention of clinicians. It can initially present as intrauterine growth restriction, being small for gestational age, or failure to appropriately progress along the growth curve. In adults, the disproportionate short stature tends to be marked and more pronounced in females (8). Our patient’s height of-4 standard deviations below the mean is average for women with PKND.

Osteosclerosis is present in all patients with PKND. While patients universally demonstrate radiographic evidence of osteosclerosis at the time of diagnosis, the clinical significance can vary considerably. The fracture rate tends to be moderate on average, with one study reporting a fracture rate of 0.2 fractures per year (9). However, patients often report no history of fractures at the time of diagnosis even as an adult (10). Unfortunately, as the present case demonstrates, investigation for an underlying sclerosing bone disorder in patients with complications of bony enlargement or a history of fragility fractures is often insufficient to prompt genetic testing and appropriate diagnosis. Indeed, the presence of diffuse sclerosis, cortical thickening, and acro-osteolysis on plain radiographs in the setting of other common clinical features is often sufficient to make the diagnosis.

The disorder presents with an array of other skeletal complications beyond osteosclerosis. Acro-osteolysis is the second most common skeletal complication present at the time of diagnosis in the vast majority of cases (9). The high prevalence of this relatively unique radiographic finding in patients with PKND underscores the importance of a thorough radiographic workup in patients with features of sclerosing bone disorders. Plain radiographs of the skull, bilateral hips, femurs, hands, and feet obtained at our initial encounter with the present patient interpreted by a musculoskeletal radiologist were sufficient to propose a diagnosis of PKND even in the absence of other important clinical history. In the absence of familiarity with the disorder, other bony abnormalities recognized on plain radiographs can lead the clinician to diagnosis. These features include open fontanels, delayed fusing of skull sutures, wormian bones, craniostenosis, and hypo-pneumatized or non-pneumatized mastoids or paranasal sinuses (9,11).

Perhaps the most pronounced phenotypic features outside of the disproportionate short stature in patients with PKND are the typical facial features and teeth abnormalities. No single feature is present in every patient, but each is present in about half of patients (9). Micrognathia is the most common facial abnormality, followed by frontal bossing, mandibular hypoplasia, aquiline nose, proptosis, maxillary hypoplasia, and blue sclera. Teeth malposition or overload, as in the present case, is noted in the majority of cases and often results in a significant history of dental and oral surgery procedures.

It is important to note the positive family history in our patient. Consanguinity is present in many reported cases, and the disease has been noted in clusters where consanguinity is more common (3,8,9). It is unclear in our patient if her positive family history had been elicited in the past, but it is an important clue that the patient may have a genetic disorder and require specialty referral.

The importance of proper diagnosis in patients with PKND cannot be overstated. While there are no targeted treatments for the disease, and the osteosclerosis does not benefit from hematopoietic stem cell transplantation (12,13), these patients require extensive specialty care over their lifetime and benefit from a multidisciplinary treatment approach. Additionally, as more cases of PKND are recognized, and the phenotypic features are better characterized, there is increasing emphasis on the need for appropriate surveillance (8). Perhaps most pertinent is the need to screen these patients frequently for obstructive sleep apnea, which is highly prevalent among adults with this disease and can be severe at an early age (14,15). Additionally, a large number of these patients develop chronic pain in early adulthood (8), which further emphasizes the need to diagnose patients with PKND to give them accurate information about disease prognosis and improve quality of life. The defective bone resorption by osteoclasts in this disease results in disordered bone remodeling and skeletal abnormality.

CONCLUSION

Diagnosis of PKND is strongly implied by clinical and radiographic findings, but genetic testing should be performed to confirm diagnosis. Treatment should consist of a multidisciplinary approach to address concerning symptoms to improve the patient’s quality of life.

Abbreviations

CTSK

cathepsin K

PKND

pyknodysostosis