​A 15-year-old boy has had joint pains for 14 years. What is the problem?

*This article is only for medical professionals to read for reference.
This disease is rare, but it cannot be ignored! In line with the original intention of "spreading the strongest rheumatism and creating a new academic fashion", on the occasion of leaving the old and welcoming the new, the "medical world" media teamed up with nearly 20 well-known experts in the field of rheumatism from the four top rheumatology departments in China, covering 8 rheumatism In the field of hot diseases, we will start the "Rheumatism and the Waves-2020 Annual Rheumatism Inventory".

In this issue, Dr.
Li Shu from the Second Xiangya Hospital of Central South University brought us "Analysis of Difficult Cases of Rheumatism".

Case brief introduction The patient, a 15-year-old male, was admitted to the hospital with a complaint of "progressive joint swelling, restricted mobility for 14 years, and worsening for 2 years".

The patient’s medical history is as follows: Past history: "Newborn jaundice" appeared after birth in 2001, and improved after treatment; in 2002, "patent ductus arteriosus closure" was performed; vaccination was required by the local epidemic prevention department.

Others: go to school at a normal age, average grades, alive parents, one sister, both healthy, denying family history of genetic disease
Admission examination: T: 36.
7℃, P: 78 beats/min, R: 18 beats/min, BP: 135/74mmHg; good nutrition, scattered acne on the face, no cyanosis of the lips, non-pitting swelling of both calves; clubbing in both hands Fingers, wrists, elbows, knees, ankle joints are swollen, tender, and limited in flexion and extension; both hips are limited in flexion, extension, abduction and extension; spine can be moved, double 4-character sign (+/-).

The picture shows the patient's physical examination characteristics and admission diagnosis: what is the cause of joint swelling and pain, congenital heart disease (after patent duct closure)? What is the cause of joint swelling and pain? Inflammatory joint disease or inherited metabolic bone disease? Complete related examinations after admission: Routine examinations: three routine tests, liver and kidney function electrolytes, blood lipids, blood glucose and myocardial enzymes are all normal, ESR 31mm/h↑, CRP 10.
2mg/l↑, RF+anti-CCP+ANA+ENA+self-immune liver +Vasculitis+ANCA: Negative, HLA-B27: Negative.Metabolic endocrine examination: three items of thyroid function, growth hormone, and insulin-like growth factors are normal, alkaline phosphatase: 217.
1u/L↑, three items of bone mark: osteocalcin 188ng/ml↑, β-collagen special sequence 3568pg/ml ↑, total type I collagen N-terminal extension peptide 638.
6ng/ml ↑, bone density: within the range of normal people of the same age.

 Other examinations: Electrocardiogram: normal, B-ultrasonography: slightly enlarged spleen, gallbladder polypoid, EMG: the upper and lower limbs electromyography and neuroelectricity showed that the amplitude of the proximal movement of the double common peroneal nerve decreased, and the double superficial peroneal nerve sensory wave No extraction (swelling of both lower limbs), X-ray head, lumbar spine and chest radiographs showed no obvious abnormalities.

X-ray hands: bone absorption at the end, X-ray hip joint: local density of the acetabulum is increased, with rough edges, X-ray lower limbs: thickening of the cortical bone of both lower limbs, abnormal shaping of both lower limbs, and changes in the bone marrow cavity.

MR plain scan: sacroiliitis; medial collateral ligament, lower end of patella and subpatellar fat pad injury, consider jumping knee; left knee joint anterior cruciate ligament injury; 3.
left knee joint effusion.

The left X-ray of both hands, the right X-ray of the hip joints are both lower limbs.
The X-rays are MR examinations.
Dr.
Li Shu summarized the patient’s case characteristics: joint swelling and pain, limb swelling, clubbing, increased ESR and CRP, and a history of congenital heart disease.
Combined with the above medical history and relevant examination prompts, what kind of disease is the patient? At present, considering the following four diseases, let’s analyze them one by one: 1.
Juvenile idiopathic arthritis (JIA): Unexplained joint swelling in childhood lasts for more than 6 weeks, and is unified as juvenile idiopathic arthritis.

Although the patient was young at onset, had multiple joint pain, and had high inflammation indicators, but RF, anti-CC antibody, ANA, ENA, HLA-B27, etc.
were all negative, and although the patient had a long course of disease, no joint space narrowing was found.
Symptoms such as bone destruction.
In addition, JIA cannot explain the history of congenital heart disease, so JIA diagnosis is not supported for the time being.

2.
SAPHO syndrome: SAPHO syndrome is a chronic disease that mainly affects the skin, bones and joints.

SAPHO is the abbreviation of the following 5 English words, namely: synovitis, acne, pustulosis, hyperostosis and osteomyelitis.

Sacroiliac arthritis in SAPHO syndrome is unilateral in about 50%, and often involves the sternoclavicular and sternocostal joints.
This patient has no typical palmoplantar pustules, and sacroiliac arthritis is bilateral without involving the sternal lock and The diagnosis of the sternocostal joint is temporarily not supported.

3.
Acromegaly: The patient's endocrine hormone levels are normal, so the disease is not considered.

Is it possible that it is hypertrophic osteoarthropathy (HO)? Let's first understand what exactly is HO? It is characterized by clubbing (toe) and tubular periosteal hyperplasia; divided into primary hypertrophic osteoarthropathy (PHO) and secondary hypertrophic osteoarthropathy (SHO); clinical SHO is more common, accounting for 95%, mainly Secondary to cardiopulmonary disease, malignant tumor or carcinoid syndrome, etc.

This patient has no cardiopulmonary disease, malignant tumor or carcinoid syndrome, so it is considered as PHO: also known as thick skin periosteal hyperplasia (PDP) or Touraine-Solente-Gole syndrome; only 5% of HO; it is a major involvement Autosomal recessive inherited diseases of skin and bones; in the classification of inherited bone diseases, it belongs to osteopetrosis in which increased bone density involves the metaphysis and/or backbone; according to the affected tissues, it is clinically divided into three subtypes: complete type : Typical clubbing, progressive skin thickening and periosteal hyperplasia; incomplete type: obvious periosteal hyperplasia but not obvious skin thickening; atypical: obvious skin thickening but not obvious periosteal hyperplasia.

The picture shows the clinical features of PHO.
The picture shows the clinical manifestations of PHO.
The hereditary PHO is rare.
What is the pathogenesis? Primary PHO is a rare autosomal recessive single-gene inherited disease.
Studies have found that its mechanism is mainly through affecting the degradation of prostaglandins and leading to the development of the disease.

The degradation of prostaglandins in the body requires two steps: transport and degradation.

Due to the mutation of the gene encoding 15-hydroxyprostaglandin dehydrogenase (HPGD) or organic anion transporter family 2A1 (SLCO2A1), prostaglandins, especially PGE2, are significantly increased locally; the prostaglandin degradation process in the figure shows that the mutant genes can be divided into 1 Types and Type 2: Type 1 is a mutation in the HPGD gene, leading to abnormal prostaglandin degradation; Type 2 is a mutation in the SLCO2A1 gene, which causes abnormal prostaglandin transport, and ultimately leads to increased local prostaglandin E2 (PGE2) expression.

Type 1 usually onset after birth, with a median age of 8.
5 years, no facial manifestations or slight patent ductus arteriosus and delayed cranial suture closure; Type 2 mostly onset in adolescence, with a median age of 15 years, with severe head and facial skin manifestations, 1 /3-1/2 gastrointestinal ulcers or bleeding.

So, what are the consequences of increasing PGE2? The picture shows the role of PGE2 to understand the PHO, analyze this case again: adolescent male, onset after birth; clubbing, limbs with thickened periosteum, accompanied by acne, hyperhidrosis; no obvious bone destruction; there is no arterial duct Closed; parents married with close relatives.

PHO is currently being considered, but HPGD and SLCO2A1 gene sequencing is needed to clarify the disease classification.
Through further genetic testing of the patient, it is finally confirmed that the patient is primary type 1 PHO caused by HPGD gene mutation.

Therefore, the final diagnosis of the patient is: 1.
Primary hypertrophic osteoarthropathy (often hidden type 1 incomplete type) 2.
Congenital heart disease with patent ductus arteriosus occluded after treatment of PHO, symptomatic treatment is sufficient The diagnosis is clear, how to treat it? There is no good strategy; to improve symptoms: non-steroidal anti-inflammatory drugs reduce the level of PGE2 in the body by inhibiting the synthesis of PGE2; skin hyperplasia affects appearance and function: plastic surgery treatment; all treatment methods cannot change the course of the disease; the pathogenesis of PHO is clear, so The treatment plan is also by inhibiting the increase of PGE2 as the main target, so celecoxib is given as anti-inflammatory and analgesic, omeprazole and hydrotalcite to protect the stomach.

After treatment, the patient's skin thickening, periosteum thickening, and joint pain were significantly reduced compared with before, and no obvious adverse reactions occurred.

Follow-up found that the thickness of the patient's forehead skin and the thickness of the right radius periosteum decreased.

The picture shows that at the end of the patient’s follow-up examination, Dr.
Li Shu also put forward his own experience of this case: 1.
HO diagnosis is not difficult: clinically, I met patients with typical clubbing, facial skin thickening, and long bone periosteum thickening.
X-ray examination of long bones is easy to diagnose the disease.
However, many patients with insidious onset in the clinic require more detailed medical history and physical examination.

2.
Enhance everyone's understanding of hypertrophic osteoarthropathy through this case, and reduce the misdiagnosis and missed diagnosis of this type of disease. Expert discussion In the final discussion session, online audiences raised some questions about PHO.
For example, when a patient enters a stable period when he is asymptomatic in adulthood, how to judge this stable period? What should be paid attention to during follow-up? In response to these questions, Dr.
Li Shu answered, "In view of the rarity of PHO disease, there is currently no big data research in clinical practice.
Although PHO is a genetic disease and has adolescent onset, the patient will spontaneously relieve after 5-20 years.
Limitations.
Observe the patient’s clinical symptoms such as skin thickening, periosteum hyperplasia, gastrointestinal tract and other stable performance.
Continue observation and regular follow-up.
The
current treatment of PHO advocates symptomatic treatment, and no treatment can change the course of the disease.

"Expert Introduction Dr.
Li Shu Attending physician in the Department of Rheumatology and Immunology of the Second Xiangya Hospital of Central South University, Ph.
D.
Director of the Rheumatology Branch of Hunan Health Service Association Graduated from the First Affiliated Hospital of Sun Yat-Sen University in 2011.
Received a doctorate in internal medicine.
Published five SCI papers as the first author.
1 Natural Science Youth Fund, 1 Natural Science Youth Fund of Hunan Province, 2 other scientific research projects.

Participated in the editing of 4 medical books