Aase-Smith syndrome type 2 with new neurological findings

Abstract

Aase-Smith syndrome type 2 is a rare genetic disorder that affects erythropoiesis and bone development, causing hypoplastic anemia and abnormalities in the fingers and toes, specifically triphalangeal thumbs. While there is no cure, treatment involves managing symptoms through blood transfusions, surgical intervention, and genetic counselling. A 15-year-old student presented with an unmeasured fever for two months, recurrent lung infections, difficulty in speech, and impaired gait. The patient had multiple congenital malformations including triphalangeal thumbs and a history of mild anemia. Bone marrow biopsy revealed an isolated slowing of erythroid lineage maturation. Radiology studies showed scoliosis, hand deformities, and multiple calcified lesions in the brain. The patient’s fever exacerbated, and oxygen saturation deteriorated, necessitating tracheal intubation. Several hours later, the patient passed away.

Introduction

Aase-Smith syndrome type 2, which is also referred to as hypoplastic anemia and triphalangeal thumbs syndrome, is an uncommon genetic disorder that affects various parts of the body. The condition is characterized by deficient red blood cells development leading to anaemia, and skeletal deformities, particularly in fingers and toes. It was initially identified by Smith and Aase in 1969 [1], and it is considered extremely rare. The syndrome affects both sexes, and symptoms typically manifest shortly after birth [2].

Individuals with Aase-Smith syndrome type 2 may experience a wide array of symptoms that can vary significantly [3]. Common features include lethargy, pallor, short stature, and unusual positioning of the thumbs. Additionally, hearing loss, cleft palate, and other developmental anomalies may be present [4]. The anaemia is thought to be due to insufficient development of the erythroid lineage in bone marrow, which results in hypoplastic anemia [5].

Currently, no cure exists for Aase-Smith syndrome type 2, and symptomatic relief is the primary focus of treatment. Blood transfusions may be necessary to address the anaemia [6]. Surgical intervention may be required to correct abnormalities in the thumbs and joints. Genetic counselling is also recommended for those affected and their families. Early diagnosis and appropriate treatment can assist individuals with Aase-Smith syndrome type 2 in managing their symptoms and living fulfilling lives. We describe a 15-year-old male with Aase-Smith type 2 syndrome, characterized by triphalangeal thumb and congenital isolated retardation of erythroid lineage maturation. Novel skeletal and neurological features are described.

Case presentation

A 15-year-old student presented to National University Hospital (Damascus, Syria) with an unmeasured fever for two months, enlarged face and flank bruises. There was no anorexia or weight loss. In the last two months, patient suffered from recurrent lung infections, which required multiple hospitalizations. Patient had also difficulty with speech and impaired gait that started approximately 18 months ago.

Parents reported a history of chronic fatigue in his childhood and held old lab documents suggesting that he had mild anaemia three years ago (RBCs 3,29 million/cm³, haemoglobin 11 mg/dl). Gestational and neonatal history was positive for postnatal blood transfusion for no clear reason. Parents are third-degree relatives, and patient had apparently healthy siblings. Patient had multiple congenital malformations, while his mental development and cognitive ability were normal. We found no present or past similar complaints in family history, but the mother has mild fingers malformation, with no proven family history of anaemia or related disorders. Medication history of the patient included (Prednisolone 15 mg/day) for the past eight months, prescribed by a private practitioner. Other medications are domperidone, vitamin E, and chlorpromazine which was stopped a month before presentation. He has no previous surgical or allergic history.

Upon examination, the patient measured 154 cm in length and weighed 55 kg. He was in a moderate general state. The heart rate was 99 beats per minute, and oral temperature was 38°C (100.4°F). In addition to paleness, he had Cushing’s facies which went along with the history of corticosteroids. We noticed bruises on the flanks and lateral sides of the thighs. Patient had multiple deformities, including bilateral triphalangeal thumbs, clinodactyly, and absent knuckles. An abnormal convergence of palmar dermal ridges was also present. Feet deformities included abnormal distal phalanx flexion of all toes and bilateral first and forth toe lateral deviation. Scoliosis was discovered by physical examination and proven by imaging later. Genitalia were normal in appearance. Abdominal examination revealed hepatomegaly (liver span = 18 cm) and an enlarged spleen (10 cm under the costal margin). Skeletal deformities are depicted in (Fig. 1). Neurological examination srevealed dysphasia, impaired gait that can be described as waddling gait, and hands tremor when raised. Meningeal signs were negative. No palpable lymph nodes were detected. Examination of other systems was normal.

The patient was admitted for further study; all medications were stopped upon admission, gradually for prednisolone. Lab and radiographic studies were ordered. The chest X-ray, ECG, echocardiography, and transoesophageal echocardiography (TEE) were also normal. A negative blood culture after double checking excluded endocarditis as a cause for the fever. Urine microscopic and strip analyses were also normal. Cerebral spinal fluid (CSF) analysis showed no abnormal findings. The Wright test and Brucella antibody analyses were both negative (for IgM and IgG). Liver function tests and kidney function tests were within reference ranges as well. Both direct and indirect Coombs tests were negative, and antineutrophil cytoplasmic antibodies C (ANCA-C) and P (ANCA-P) were 4.9 U/ml, and 1.3 U/ml, respectively. Complete blood counts showed normocytic anaemia with an RBCs count of (3.06 million/cm³), Haematocrit (23.9%), MCV on the normal minimum (78 fl.), reticulocytes (3.5%), haemoglobin (8.82 mg/dl) and MCH (27.1 pg.). WBCs counted (1130/cm³), Neutrophils (31%), Lymphocytes (62%), platelets (35 000/cm3) and RDW (20%). Hemoglobin electrophoresis was normal, for ferritin (1202 ng/ml) and Iron (28 mcg/dl). LDH was elevated (804 U/l). Plasma protein electrophoresis was normal.

Further hematologic studies were necessary to investigate the pancytopenia. The adenosine deaminase test came back negative, and glucose-6-phosphate dehydrogenase (G6PD) deficiency was also excluded. Negative PCR and normal chromosomal breakage test excluded Fanconi anemia. Bone marrow biopsy was hypocellular compared to the age with slowed erythroid lineage maturation and normal megakaryocytic lineage. The myeloid to erythroid ratio was (10:1). Karyotype was normal (46 XY).

X-ray imaging showed hand deformities as bilateral triphalangeal thumbs whose bones are abnormally configured. Multiple accessory bones in metacarpal phalangeal articulations. The distal radius and ulna were normal. Thoracic scoliosis was also proven with an X-ray (Fig. 1). Abdominal ultrasound confirmed hepatomegaly and splenomegaly with normal pancreas. Pre- and post-gadolinium MRI series showed a multitude of tiny-sized, enhancing, partially calcific miliary lesions diffusely scattered in both cerebral and cerebellar hemispheres (Fig. 2). Multiple sclerosis was excluded by negative oligoclonal ban test of CSF, negative electromyography and insignificant nerve conductance study.

During the twelve days of admission, the patient fever exacerbated, which demanded the re-administration of prednisolone, after which the fever was relieved. Also, the patient received four units of platelets and two units of whole blood as a preparation for diagnostic procedures, not for haemorrhagic indication or a drop in blood components. Throughout his stay in the hospital, the patient acquired a severe respiratory infection that needed antibiotic treatment with vancomycin, tazobactam, and meropenem; Bactrim (sulfamethoxazole and trimethoprim) was added later. Oxygen saturation deteriorated and the patient was intubated. Several hours later patient died.

Discussion

Aase-Smith type 2 syndrome is an extremely rare syndrome, first reported in 1969 [1]. Since then, only a handful of cases have been described. Aase-Smith type 2 syndrome is defined as a variety of congenital hypoplastic erythropenia syndrome (Diamond-Blackfan anemia) but accompanied with triphalangeal thumb. This syndrome may be accompanied with other malformations as well [7]. In our case, the patient had isolated inhibition of erythropoiesis and malformations of all fingers and toes including the triphalangeal thumb. In addition, he had thoracic scoliosis, cerebral and cerebellar calcifications, newly developed impaired gait, and recently noted dysphasia. These characteristics have not been previously described.

One of the most notable and distinguishable features of this syndrome is the presence of triphalangeal thumb [8]. In this case, the patient was found to have a right triphalangeal thumb. Presence of these thumb deformities is attributed to abnormalities in the limb buds during embryogenesis [8]. The current case of Aase syndrome presents with additional limb and skeletal malformations, including scoliosis and deformities of the fingers and toes, as previously reported in other studies [2]. Apart from the limb malformations, Aase-Smith type 2 syndrome is mainly a hematologic disease characterized by inhibition of the erythroid lineage. Leukopenia and thrombocytopenia in our patient can be explained by the hepato- and splenomegaly that are common among hematologic patients. Thrombocytopenia and leukopenia were also reported elsewhere [9]. The exact mechanism behind these hematologic abnormalities is not known.

The use of bone marrow biopsy is a crucial diagnostic tool for Aase-Smith type 2 syndrome [10]. Our biopsy results indicate a reduced cell count relative to the patient’s age and a slow maturation process of the erythrocyte lineage. However, the defect in the maturation process was not detected at a specific stage, and there were no abnormalities in the megakaryocyte or lymphoid lineage. This finding corresponds to a previous study of two children where one child had a pre-BFU-E level maturation defect and the other child had a post-CFU-E level maturation defect [9]. Further research is required to understand the exact mechanism by which Aase-Smith type 2 syndrome impacts erythropoiesis.

There is some evidence to suggest that Aase-Smith syndrome may be inherited as an autosomal recessive trait, although more studies are needed to confirm this hypothesis [3, 8].

This case is noteworthy due to the first-to-describe cerebral calcifications. We could not study the pathology of these calcifications well, but we could exclude multiple sclerosis. This case underscores the need for continued research and comprehensive reporting to better understand rare genetic disorders, potentially leading to improved management of such conditions.

Treatment of Aase-Smith type 2 syndrome is mainly supportive and includes regular blood transfusions to correct anemia. In addition, treatment may include surgical correction of limb deformities and scoliosis. However, there is no curative treatment for this syndrome, and the prognosis is variable depending on the severity of the malformations and hematologic abnormalities [2, 7]. It is important to note that there is no known cure for Aase-Smith type 2 syndrome, and treatment is focused on managing the symptoms and complications associated with the condition. The outlook for individuals with Aase-Smith type 2 syndrome varies depending on the severity of their malformations and hematologic abnormalities. While some individuals may experience mild symptoms and live relatively normal lives, others may have more severe symptoms that significantly impact their daily functioning.

In conclusion, Aase-Smith type 2 syndrome is an infrequent genetic disorder that presents diverse malformations such as facial anomalies, scoliosis, and thumb deformities. The diagnosis of this syndrome poses a challenge, requiring a high level of suspicion, particularly in patients displaying anemia and thumb deformities. Utilizing bone marrow biopsy is essential in diagnosing Aase-Smith type 2 syndrome, and regular blood transfusions remain the fundamental treatment option. Furthermore, it should be noted that the syndrome under consideration is of the second type in this report, distinct from the one originally identified in 1968 as type 1 [11]. More research is necessary to clarify the precise mechanisms responsible for erythropoietic defects in this syndrome and to develop more efficacious therapeutic interventions for this uncommon pathology.

Conclusion

Aase-Smith type 2 syndrome is a rare genetic disorder manifesting as isolated red blood cells hypoplasia, triphalangeal thumbs and various skeletal malformations like facial anomalies. Diagnosis is challenging, requiring a high level of suspicion, particularly in patients displaying anemia and thumb deformities. Bone marrow biopsy is essential for diagnosis, and blood transfusions is the standard of care. Our case has new neurological (cerebral calcifications) and skeletal findings. Aase-Smith type 2 syndrome is distinct from type 1, identified in 1968. Further research is necessary to clarify the mechanisms responsible for erythropoietic defects and develop better therapeutic interventions.

Acknowledgements

No acknowledgement is to be made.

Conflict of interest

There is no conflict of interest to disclose.

Funding

All authors have declared that no financial support was received from any organization for the submitted work.

Ethical approval

Ethical approval for publication has been obtained.

Consent

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent will be available for review if asked by the editor-in-chief of this journal.

Guarantor

Ziad Aljarad.

References

Author notes