Pathological fracture of the femur in Alagille Syndrome: A case report

Abstract

Alagille Syndrome is a rare autosomal dominant genetic disorder, occur only 1:70,000 in population, and characterized by reduced interlobular bile ducts, and resultant nutritional deficiencies associated with the inability to absorb fat-soluble vitamins such as vitamin D. Patients are at risk for secondary osteoporosis, rickets/osteomalacia, and ultimately may result in fracture. The majority of patients suffer from chronic cholestasis, which can have a variety of adverse effects on bone metabolism. Hypothyroidism has been described in some Alagille Syndrome patients, and eventually delayed puberty can occur. Two until fourteen percents of patients of Alagille syndrome will suffer from fractures, in which it primarily occurs in the lower limb long bones in the absence of significant trauma. This study aimed to present a rare case of pathological fracture of femur in Alagille syndrome patient and its management in our hospital.

Six-year-old male with pain on his right thigh came to our ER after fell down while putting on his pants. He had been diagnosed with biliary atresia at the age of 3 months and underwent surgical bile duct reconstruction. In addition, he also suffered from congenital hypothyroidism and consequently, stunted growth. The pathological fracture of the femur was treated conservatively with hemispica cast. At 2 months follow up, there is already radiographic evidence of fracture healing occurred by secondary intention and callus formation.

By ensuring adequate calcium and vitamin D intake, monitoring for vitamin D deficiency, monitoring for fragility fractures, and avoiding trauma-related accidents, a proper conservative treatment using hemispica cast could still always be considered for managing such diaphyseal fractures in Alagille syndrome, especially in relatively low-resource countries such as Indonesia.

1. Introduction

Alagille Syndrome was first described by a French Pediatrician, Daniel Alagille in 1969 as a multisystem disorder with the primary problem of intrahepatic bile duct paucity. It is considered positive when there are three or more manifestations of the major criteria, which are chronic cholestasis, cardiac disease, ocular abnormalities (posterior embryotoxon), skeletal abnormalities (butterfly-like vertebrae), and peculiar facial features.¹ It also has many minor criteria due to its highly variable expression of the JAG1 gene mutation (locus 20p12.2) or in a few patients, a NOTCH2 gene mutation (locus 1p12-p11).²

Alagille syndrome has an autosomal dominant inheritance pattern, only affecting around 1 in 70,000–100,000 live births. The majority of patients suffer from chronic cholestasis, which can have a variety of adverse effects on bone metabolism.³ They are at risk for secondary osteoporosis, rickets/osteomalacia, and ultimately may result in a pathologic fracture. It primarily occurs in the lower limb long bones in the absence of significant trauma, although the estimated incidence is relatively small, only about 2–14% of patients of Alagille syndrome.⁴ This study aimed to present a rare case of pathological fracture of femur in Alagille syndrome patient and the outcome of this case management in our hospital.

2. Case report

A 6-year old boy came to our Emergency Room with pain and deformity on his right thigh after slipped and fell down while putting on his pants. He has never had the same symptoms before and appeared considerably unwell. He has a history of cholangiectomy on 3-month age with the diagnosis of Inpissated Bile Duct Syndrome at that time. Physical examination revealed an icteric skin with a prominent forehead, deep-set eyes, moderate hypertelorism, upslanting palpebral fissures, and pointed chin. There was no abnormality in the cardiac and respiratory system, and also no ascites was found. In his right thigh, we found posterior angulation with 2-cm leg-length discrepancy (Fig. 1).

Fig. 1.

Clinical picture of the craniofacial and affected thigh at the ER

X-Ray of the right thigh showed complete cortical discontinuity of the middle part of the femoral shaft, with the displacement of the distal part medially and posteriorly. Later in the ward, we added a thoracolumbar X-ray, in which it reveals a sagittal cleft in the vertebral body of the sixth thoracic vertebrae, a phenomenon called “butterfly vertebrae” (Fig. 2). Abdominal ultrasonography shows no visible abnormalities in abdominal viscera, except contracted gallbladder with sludge in it.

Fig. 2.

X-ray findings of right thigh AP & Lateral View, and AP radiograph of the thoracic spine.

Laboratory investigation revealed a more dominant conjugated hyperbilirubinemia (Total bilirubin 35.49 mg/dL, direct bilirubin 25.55 mg/dL, Indirect bilirubin 9.94 mg/dL), and a more dominant increase in Alkaline Phosphatase (532 U/L) than Alanine Transaminase (86.7 U/L) and Aspartate Transaminase (182.8 U/L), indicating a cholestatic disease. There was also slight subclinical hypothyroidism (TSHS 4.31 IU/ml, T3 1.69 nmol/L, FT4 1.59 ng/dL) which was also a minor clinical feature of Alagille syndrome, and might explain his slightly stunted growth. Other abnormalities found was hypocalcemia (8.1 mg/dL) and deficiency of calcifediol (13 ng/ml).

Our management consist of both local and systemic situations. Systemically, the patient was given Propranolol to lower hepatic portal pressure and prevent ascites formation, Ursodeoxycholic Acid as a choleretic agent to improve the bile flow, multivitamin (Apialys Syrup) with additional Calcium tablet, Vitamin E, and Vitamin K. We also ensure that the patient received proper and optimized dietary input with supplementary feeding.

Locally, we do early hemispica cast under fluoroscopy to achieve accurate anatomical reduction. At one-month follow-up, we found a slight loss of reduction but still acceptable (8° of varus, 7° of posterior angulation) (Fig. 3). At two months, there has been a clinical union, while radiographically there has been an abundant callus formation with acceptable alignment (8° of varus, 7° of posterior angulation) (Fig. 4), therefore the cast was removed and physical rehabilitation program was started. At four months postoperative, the patient has already anatomically and functionally recovered.

Fig. 3.

AP & Lateral radiograph of the right thigh one-month post reduction.

Fig. 4.

AP & Lateral radiograph of the right thigh two-months post reduction.

3. Discussion

Alagille Syndrome is a rare disease, occurring only about 1 in 70,000–100,000 live births. The pathological fracture in the disease is also an uncommon occurrence, estimated only in 2–14% of its patient⁴ In theory, there is 2 closely-linked pathophysiologies for the pathological fracture. The high level of bilirubin due to intrahepatic bile duct paucity will inhibit the proliferation of osteoblasts, in which it will induce systemic osteopenia and subsequent osteoporosis at long-term. Also, chronic cholestasis due to intrahepatic bile duct paucity will lead to the deficiency of intestinal bile acid, in which it will negatively affect the absorption of calcium and fat-soluble vitamins (Vitamin A, D, E, K). This entangled mechanism will eventually lead to the pathologic fracture in Alagille syndrome.⁵

Up until now, there is still no clear consensus regarding how the best treatment is in pediatric diaphyseal femoral fracture, let alone in pathologic fracture due to metabolic disease such in this case. The management of diaphyseal femoral fracture in children varies from non-operative treatment using Pavlik harness, Gallows traction, and spica cast; until operative treatment using plate-screw, and rigid or flexible intramedullary nailing.⁶ The most recent AAOS guideline showed moderate evidence to support the use of spica casting, whether it is early or delayed, in the management of femoral shaft fracture in children below age 6, while there is still limited evidence to support the use of submuscular plating, rigid or flexible intramedullary nailing in older children.⁷

A recent, featured article from the UK, also advocates the use of conservative treatment for diaphyseal femoral fracture in children, in which it already considered as a “lost-art”.⁸ Indeed, in such pathologic fracture, there might be some impairment of the normal bone healing process. Hence Nozaka et al. used an Ilizarov ring fixator combined with low-intensity pulsed ultrasound stimulation device for the treatment of a similar patient. Indeed, the patient has already achieved union in less than 2 months and the normal function of the affected limb in just 74 days.⁹

As the first general principle of treatment, the great Robert Bruce Salter advocated the principle of “first, do no harm”, which was initially told by Hippocrates nearly 2000 years ago.¹⁰ Regarding this case and its related literature, one should also aware that the bad results of ORIF are also worse than the worst results of closed reduction. Therefore, spica casting is still a feasible option for children of his age, with additional advantage regarding the economic reason and decreased hospital length-of-stay. Due to his impairment on bone healing, the anatomical reduction was aimed using the fluoroscopy, instead of bayonet apposition.

As we carefully maintain the systemic condition of the patient, the bone healing itself is eventually minimally impaired, and in 2 months there was already an abundant callus formation and subsequent clinical union. At 4 months, he already walk normally with practically full range of motion at hip and knee joint. A further, long-term follow-up is indeed still needed to ensure comprehensive and holistic treatment for the patient, so that he would lead productive lives unaffected by the complications of the syndrome.

4. Conclusion

Patients with Alagille syndrome have to be followed in a serious way because of the high risk of complications, in this case a pathological fracture of the femur. Proper conservative local management with adequate systemic management could still always be considered as a viable option for treating fractures in such metabolic bone disease, especially in relatively low-resource countries, such as Indonesia.

Source(s) of support

There is no any funding regarding to this research.

Authors contribution

I.K.S. performed the surgery. M.A.M. helped with surgery and helped to draft the manuscript. H.K.N. helped draft the manuscript. All authors read and approved the final manuscript.

Declaration of competing interest

There is no conflict of interest in this study.