Lowe syndrome is a rare, X-linked recessive disorder caused by mutations in the
The clinical findings and results of genetic studies were reviewed for 12 male patients diagnosed with Lowe syndrome at a single medical institution.
The mean age of the patients at presentation was 2.2 months (range, 0-4 months), although the diagnosis was delayed by a mean of 2.8 years (range, 0-9.7 years). The mean follow-up period was 9.0 years (range, 0.6-16.7 years). Nine mutations in
This study describes the clinical and genetic characteristics of Korean patients with Lowe syndrome. The observations are helpful for understanding the natural courses of Lowe syndrome and for appropriate genetic counseling.
Lowe syndrome (OculoCerebroRenal syndrome of Lowe) is an X-linked, recessive disorder characterized by congenital cataracts, mental retardation, and proximal renal tubular dysfunction (Fanconi syndrome)
The clinical manifestations vary among affected individuals and also according to their age. Bilateral cataracts are present at birth and are associated with glaucoma in approximately half of the affected males, often resulting in progressive visual loss
This syndrome is caused by mutations in the
A total of 12, unrelated, male patients with Lowe syndrome were included in this study and had been referred from the Department of Pediatrics, Medical Genetics Center, Asan Medical Center Children's Hospital, Seoul, Korea, from December 1991 to April 2013. The demographic data, clinical manifestations, and the results of multidisciplinary studies, i.e., ophthalmologic, otolaryngologic, orthopedic, and urologic, were reviewed. Informed consent allowing genetic studies was obtained from all of the parents or guardians of all of the study patients.
The clinical diagnosis of Lowe syndrome was based on the presence of all three of the following: (1) congenital bilateral cataracts; (2) renal Fanconi syndrome; and (3) involvement of the central nervous system, such as hypotonia and mental retardation
Mutation analysis was carried out using genomic DNA from peripheral blood using a QuickGene DNA whole blood kit (Fujifilm, Tokyo, Japan). Twenty-three exons, including coding sequences of the
The first presenting sign of Lowe syndrome in all 12 patients was bilateral congenital cataracts. The mean age at presentation was 2.2±1.8 months (0 to four months of age). However, clinical diagnosis of Lowe syndrome was delayed until 51.3±61.9 months of age (four months to 18 years of age). The interval from presentation to diagnosis was 34.1±34.8 months (0 to 116 months). At diagnosis, delayed development was seen in six patients (50%). In addition, proteinuria, nystagmus, seizure or sensorineuronal hearing loss were seen in the remaining six patients (
A total of nine different
Maternal carrier status was evaluated in seven families and was positive in two mothers (subjects 5 and 9). A positive family history was noted in subject 2 whose elder brother showed bilateral congenital cataract and sensorineuronal hearing loss. The elder brother died of sepsis at 29 months of age.
All 12 patients survived during the follow-up period of 9.0±5.6 years (0.6 to 16.7 years).
All patients presented with profoundly short stature (
There was marked delay in height and BMI in all cases at diagnosis and/or at the last follow-up visit. Linear growth velocities were below normal and short stature became evident by the age of one year in all 12 patients. The mean final height of four patients was 147.4±14.9 cm (128.7 to 165.0 cm), and the onset of puberty was delayed in two patients (subjects 1 and 4).
Cataract removal surgery was performed in 11 patients at 3.6±1.6 months of age (one to seven months of age), and an intraocular lens was implanted in six (6/11, 55%) of these patients (
All patients experienced neonatal hypotonia with motor and cognitive developmental delay as well as mental retardation (
Five patients whose urinary β2-microglobulin had been measured had albuminuria including low-molecular weight proteinuria (
Hypercalciuria (9/12, 75%), phosphaturia (6/12, 50%), renal rickets (9/12, 75%), hypokalemia (4/12, 33%), and nephrocalcinosis (7/12, 58%) were noted (
Six patients (50%) experienced repeated pathologic bone fractures (
Cutaneous cysts on the buttock or back were noted in five patients (5/12, 42%), and cryptorchidism was detected in five patients (5/12, 42%).
An increased bleeding tendency was not observed during daily activities or at the time of surgery in any patient. Platelet counts, prothrombin time, and activated partial thromboplastin time were also normal in all cases.
Twelve patients in our study manifested the constellation of clinical features of Lowe syndrome. Bilateral congenital cataract is the earliest sign and requires surgery during infancy, although visual impairment can be reaggravated. Hypotonia, developmental delay, profoundly short stature, proximal renal tubular dysfunction or Fanconi syndrome and its complications such as renal rickets and nephrocalcinosis, were invariably seen in most of our study patients. However, only one patient had renal insufficiency. The small proportion of renal insufficiency in our patients is related to the short duration of the follow-up period as in Lowe syndrome chronic renal failure usually develops between the second and fourth decades of life
More than 200 different mutations in
Meanwhile, three novel mutations were detected in our study. Two frameshift mutations, p.Leu723Trpfs*4 and p.Arg596fs*10, were identified in the ASH (ASPM, SPD-2, Hydin)/Rab binding domain spanning exons 17-19. The third novel mutation, c.2408_*5164inv, was gross inversion of exons 21-23 which mapped to a region in close interaction with the ASH domain. The ASH-RhoGAP (Rho GTPase activating) module regulates the majority of the protein-protein interactions for
All patients with Lowe syndrome present in infancy with congenital cataract. However, the clinical diagnosis is established about two or three years later in most patients. Congenital bilateral cataract, neonatal hypotonia, and/or delayed development accompany other congenital syndromes due to chromosomal anomalies or prenatal infections
Profound short stature and delayed puberty were both evident in our patients. Chronic renal failure and metabolic acidosis along with renal rickets are supposed to contribute to a patient's short stature and delayed puberty. Growth impairment is also a common feature in children with Fanconi syndrome
Although most of the clinical features of Korean Lowe syndrome patients did not differ from those reported in other countries, there are some differences in our study. According to Lasne et al.
Despite the extensive studies, it remains elusive how the
Although we comprehensively reviewed the clinical and genetic findings of Korean patients with Lowe syndrome, our study has some limitations. First, the number of patients we reported in this study was too small to represent the general clinical and genetic features of Korean patients with Lowe syndrome and their genotype-phenotype correlations. In addition, the follow-up period was too short and variable among patients in order to assess the long-term natural course of Lowe syndrome in each patient. Because there is not a standardized, follow-up monitoring protocol, the clinical evaluation might have been incomplete in some patients.
Until now, a few studies have been reported on Korean Lowe syndrome. Kim et al.
We thank the patients and their families for participating in this study which was supported by a grant from the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (Grant No. 2011-0019674).
No potential conflict of interest relevant to this article was reported.
Axial brain magnetic resonance images of subject 12 at 4 years of age, showing white matter and the optic tract with high signal intensity on T2-weighted images.
Kidney ultrasonographic images of subject 2 at 10 years of age, showing echogenic medullae consistent with medullary nephrocarcinosis in both kidneys.
Clinical findings and mutations of the
NA, data not available; ND, not done.
Physical growth of the patients with Lowe syndrome
SDS, standard deviation score; BMI, body mass index; NA, data not available.
*Final height.
Ocular characteristics of the patients with Lowe syndrome
NA, data not available.
Neurological characteristics of the patients with Lowe syndrome
EEG, electroencephalography; MRI, magnetic resonance imaging; ND, not done; R/O, rule out.
Renal characteristics of the patients with Lowe syndrome
LMWP, low molecular weight proteinuria; TRP, renal tubular reabsorption of phosphate; UCa/Cr; urinary calcium/creatinine ratio; pRTA, proximal renal tubular acidosis; FS, Fanconi syndrome; eGFR, estimated glomerular filtration rate (using the Schwartz formula in patients under 18 years of age; and modification of diet in renal disease in patients [shown in *] over 18 years of age); ND, not done.
Skeletal, integumental, and other characteristics of the patients with Lowe syndrome
SNHL, sensorineuronal hearing loss; NA, data not available; ASD, atrial septal defect; VSD, ventricular septal defect; R/O, rule out.
*None, 0; <5 times, 1; ≥5 times, 2.