Primary hypertrophic arthropathy with marrow fibrosis

Primary hypertrophic arthropathy (PHO), also known as Turin Solentines-Joll syndrome (TSG) or cutaneous osteoporosis (PDP), is a rare, autosomal recessive, multisystemic genetic disorder characterized by a triad of thickening of the skin (epidermal emphysema), abnormal growth of bone and connective tissue periosteum and digital arrogance [1]. In 2008, it was determined that mutation in the HPGD gene, which codes for 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is the main cause of PHO. In 2012, another pathogenic gene was identified to be a member of the solute carrier organic anion transporter family 2A1 (SLCO2A1), which encodes the prostaglandin transporter. [2]. Manifestations usually begin at puberty and progress gradually over the years, with a wide spectrum of diverse radiological and clinical manifestations. Many cases of PHO have been reported to be complicated by life-threatening anemia and gastrointestinal complications (eg, hypertrophic gastropathy) [3]. Anemia in patients can be caused by various mechanisms, including the development of inhibitors of erythropoiesis, bone marrow failure, and blood loss mainly from the gastrointestinal tract. [4].

A 21-year-old man, residing in Punjab, Pakistan, a tailor by profession, presented to a local hospital with a seven-year history of intermittent low-grade fever (not associated with chills and chills), lethargy, general weakness, excessive sweating, body aches and joint pain. It affects large joints such as the wrist and knee joints. The patient had five siblings and the parents were in a close marriage (Fig. 1). General physical examination revealed pallor of the conjunctiva, coarse wrinkles on the forehead, prominent nasolabial folds, acne on the face, protrusion of the jaw, swelling of the bilateral wrist joints, and first-degree clubbing (Fig. 1). 2). His cardiovascular and respiratory examinations were unremarkable, and abdominal examination showed an enlarged liver and spleen, with the liver being palpable 2 cm below the costal margin (BCM) and being solid, not soft and having a smooth edge, while the spleen was palpable 4 cm BCM (non Thin, soft). His medical history was significant for transfusion-dependent anemia requiring about 90 units of red cell concentrate (RCC) over the previous six years. Since 2020, the monthly demand for RCC has increased from two to three.

Likewise, his five-year-old sister had a history of similar symptoms and dependence on blood transfusions. Clinical examination revealed pallor of the conjunctiva, frontal paresthesia, protruding jaw, clapping of the hands of the second degree, and dark skin discoloration with few dry lesions in the anterior part of bilateral lower extremities. A dermatologist was taken on board to treat the lesions on the lower extremities, which were described as enlarged sinuses. Systemic examination proved to be uneventful. She has had 11-12 RCCs in the past 5 years (~1 RCC/six months).

His complete blood picture (CP) showed hemoglobin (Hb): 4.7 g/dL, mean body volume (MCV): 96 fluid, white blood cells (WBC): 3.1 x 103/L, absolute neutrophil count (ANC): 2.6 x 103/l, platelets: 47 x 109/l on Sysmex blood analyzer (also confirmed manually). Peripheral blood smear revealed erythrocytosis, microcytosis, hypopigmentation, tear drops, 2 NRBCs per 100 RBCs, and a reticulocyte count of 1.5%. A dilute bone marrow sample was received without an evaluable fraction, whereas a trephine biopsy showed cytostatically hyper-marrow with an overall cytokinesis of ~80% and megakaryocytes forming clusters. Grade II marrow fibrosis (WHO classification of myelofibrosis) was also observed, suggesting overt myelofibrosis. Myelofibrosis (bone marrow fibrosis) was also examined for its underlying causes. Polymerase chain reaction (PCR) was performed for JAK2 (V617F), CALR (exon 9), cMPL (exon 10), and BCR-ABL1, and no mutation was detected. autoimmune profile [including antinuclear antibodies (ANA), extractable nuclear antigen antibodies panel, anti-cyclic citrullinated peptide (CCP), rheumatid Arthritis (RA) factor] were negative. Bone scans showed a diffuse increase in tracer uptake in the appendicular skeleton. All of these findings were consistent with myelofibrosis (bone marrow fibrosis).

On the basis of the patient’s history, family history, and clinical examination, the suspicion of hypertrophic osteoporosis (HOA) was raised and genetic testing was advised. The patient was found to be homozygous for the c.664G>A (p. Gly222Arg) mutation in the SLCO2A1 gene. Additional variants of uncertain significance were found in the genes COL10A1, IFT172, MESDC2, PCNT, RUNX2, SQSTM1, TONSL, TRIM37, WDR35 and WDR60. The family was also screened for the detected mutation and the results are shown in the table 1.

family

gene

zygote

symptoms

Father 57 years old male

SLCO2A1 (pg Gly222Arg)

Heterozygous

No visible symptoms

I am 52 years old female

SLCO2A1 (pg Gly222Arg)

Heterozygous

No visible symptoms

Patient 21 years old, male

SLCO2A1 (pg Gly222Arg)

symmetric

blood transfusion dependency

Brother 17 years old female

SLCO2A1 (pg Gly222Arg)

Heterozygous

No visible symptoms

Brother 15 years old female

SLCO2A1 (pg Gly222Arg)

symmetric

blood transfusion dependency

Brother 12 years old female

SLCO2A1 (pg Gly222Arg)

Not detected

No visible symptoms

10-year-old brother, male

SLCO2A1 (pg Gly222Arg)

Heterozygous

No visible symptoms

Brother 5 years old, male

SLCO2A1 (pg Gly222Arg)

symmetric

No visible symptoms

Based on all of the above features, a diagnosis of idiopathic primary PHO with an unusually severe complication of myelofibrosis (bone marrow fibrosis) was established. He started using erythropoietin and cyclooxygenase 2 (COX 2) inhibitors, which caused reduced dependence on blood transfusions.

PHO is a rare genetic disorder characterized mainly by abnormal bone formation and dermatitis and is poorly understood [5]. The pathogenetic association between PHO and myelofibrosis is still poorly known. Several mediators, including platelet-derived growth factors (PDGF), TGF-beta 1, and vascular endothelial growth factor (VEGF), secreted by platelets and alpha megakaryocytes have been identified as inducers of increased fibroblast activity. [6]. The main feature in the pathogenesis of PHO is the failure of prostaglandin E 2 (PGE2) hydrolysis. Several genes, such as HPGD, prostaglandin-endoperoxidase synthase (PTGS) 1, PTGS2, prostaglandin E synthase (PTGES), PTGER1, prostaglandin E receptor (PTGER) 2, PTGER3, PTGER4, SLCO2A1, SLCO3SL signaling in the pathway biosynthesis, PGE2 [7]. A recent analysis suggested that patients with SLCO2A1 prostaglandin transporter mutations are more likely to develop myelofibrosis (fibrosis of the bone marrow) [8].

According to our best information, only 22 cases of myelofibrosis (PHO) with myelofibrosis (bone marrow fibrosis) have been reported to date, and nine cases (40.9%) from Asian countries. [9]. Our patient had a long history of fatigue and other symptoms associated with anemia and, depending on the blood transfusion in the past year, indicated that the blood composition was well compensated at the onset of the disease. No standard treatment has been established for PHO patients with myelofibrosis. Severe anemia can be treated with a blood transfusion. A few cases have reported successful treatment of anemia with steroids and hematinocytes [10].

Although PHO is primarily a benign disorder, coexisting myelofibrosis can lead to clinically significant leukopenia. To avoid losing the diagnosis, we recommend taking detailed notes of the history from these patients along with regular clinical and laboratory examinations.

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