临床特征

Alström 综合征是临床主要表现为锥杆营养不良，肥胖，进行性感觉神经性听力减退，扩张型或限制型心肌病和胰岛素抵抗的综合征，并伴随多器官衰竭。患者临床表现多 样，即便在同一家系中都有很高的表型可变性。锥杆营养不良临床表现为进行性视力减退，畏光和眼球震颤，这些症状通常于出生到15个月间就会出现。很多患者 在20岁彻底失去光感，但部分患者可保持大字体的阅读能力至30岁。患儿常于出生时体重正常，但在出生后一年发展为躯干性肥胖。70%以上的患者在出生后 一年内表现出进行性听力减退。听力减退可在10岁至20岁发展至中等或严重水平（40-70db)。胰岛素抵抗都会伴随黑棘皮症，并于30岁左右发展为2 型糖尿病。几乎所有的患者都表现出血脂异常。其他内分泌系统异常包括甲状腺功能减退，男孩的低促性腺素型功能减退症和女孩的多囊卵巢。

超 过 60%的Alström综合征患者会出现由于扩张型和限制型心肌炎所引发的心衰。50%的患者早期发育里程碑推迟，智力正常。肝脏异常表现为转氨酶水平升 高，脂肪变性，肝脾肿大和脂肪肝。高血压和肝硬化可导致肝性脑病和威胁生命的食管静脉曲张。另外也可能会出现肺功能紊乱和严重的肾病。青少年末期可能会发 展至终末期肾病。

诊断/检测

管理

Management.

对症治疗 ：可针对畏光配红色处方眼镜，做盲目或视力减退方面的引导；健康饮食和规律运动；当出现听力下降时行鼓膜切开置管术或佩戴助听器。对 心肌病需采取抗充血措施；对于II型胰岛素拮抗型糖尿病采取常规治疗措施。高脂血采用常规的尼克酸类药物。如果青春性发育不正常需咨询内分泌专家。对排泄 困难的患者需施尿流改道术或导管术，已有一些患者被报道成功进行了肾移植手术。对门静脉高压和食管静脉曲张需采取合理的治疗方案，慢性阻塞性肺病和相关的 感染需根据业内公认指南进行治疗。

主要并发症的预防：进行性糖尿病和严重的高血糖症需通过正确的生活方式和避免过度肥胖来控制

次要并发症的预防：常规的小儿科免疫接种，在急性病和手术中需实时监控心脏状态和供氧。

需避免的药剂和环境因素：任何肾功能和心功能不全患者禁用药物；可能影响其他系统的对症治疗方案（如针对糖尿病的二苯硫卡巴腙对于心功能不全的患者是禁用的）

遗传咨询

Alström 综合征是常染色体隐性遗传病，患者的兄弟姐妹有25%的可能性是患者，50%的可能性是无症状的携带者，25%的可能性是无症状的非携带者。如果在家系中已有人确定是Alstrom综合征患者，那么建议对家系中有血缘关系的成员进行携带者筛查和产前诊断。

临床诊断

Alstrom综合征的诊断是依据婴儿期、儿童期和青年期出现的主要临床特点而做的 (见表1和图1).

图1.

Alstrom综合征不同年龄段的临床特点

患者不同年龄阶段的主要临床特点[Marshall et al 2005]：

主要特点

• 视锥杆营养不良，伴眼球震颤和畏光（光敏感/畏光）常发作于出生后第一年
• 肥胖，躯干型肥胖（BMI>25，或大于95%百分位），常出现于儿童期早期
• 进行性双边型感觉神经性耳聋在1~10岁出现，发病年龄多样。听力减退主要从高频段开始
• 扩张型心肌病于婴儿期发作或60%左右的患者于青年期或成年期发作限制型心肌病
• 肺病的症状从频繁发作的支气管感染至肺纤维化和肺动脉高压
• 胰岛素耐受/2型糖尿病，胰岛素耐受程度根据个体差异从高胰岛素血症到葡萄糖不耐受到2型糖尿病不等。2型糖尿病可能从儿童期到青年期发病。
• 肝脏方面的症状多变，从转氨酶升高到脂肪性肝炎。肝脾可能会出现扩大症状。广泛型肝硬化，纤维化，门静脉高压和肾衰都有案例被报道。
• 肾脏方面的表型是进行性的，肾小球硬化的严重程度高度可变

其他特点

• 甲状腺功能减退
• 牙齿异常（如牙釉质变色，牙位异常或额外牙）
• 宽平足
• 男性性腺功能低下症/女性雄激素过多症
• 泌尿道功能紊乱/逼尿肌不稳定
• 发育里程碑延迟，包括大运动延迟和语言表达能力延迟
• MRI异常信号（部分患者蝶鞍缺失），强直阵挛发作
• 面容异常（下置耳，圆脸，额叶内板增生，厚耳，额过早秃顶，毛发细）

据 Marshall et al [2007a]报道，诊断标准根据患者的年龄进行修订 (表 1).

Molecular Genetic Testing

Gene.ALMS1 is the only gene in which mutation is known to cause Alström syndrome.

Clinical testing

Test characteristics. See Clinical Utility Gene Card [Marshall et al 2011a] for information on test characteristics including sensitivity and specificity.

Interpretation of test results. Given the current detection rate, failure to identify a disease-causing sequence variant does not preclude the diagnosis of Alström syndrome.

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis of Alström syndrome relies primarily on clinical findings and/or family history.

• In some instances the diagnosis can be confirmed by molecular genetic testing. Sequence analysis of the coding region should be performed: tiered testing with sequencing of select exons first, followed by analysis of the entire gene.
• The frequency of deletions is unknown but deletion/duplication analysis may be clinically indicated in some instances.

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family.

Clinical Description

A wide range of clinical variability is observed among individuals with Alström syndrome, including among sibs [Hoffman et al 2005]. The first clinical presentation of Alström syndrome (Table 3) is usually nystagmus caused by cone-rod dystrophy and resulting in childhood blindness. Disease characteristics that are later in onset include truncal obesity that manifests during the first year of life, progressive sensorineural hearing loss, infantile-onset dilated cardiomyopathy or later-onset restrictive cardiomyopathy, insulin-resistant type 2 diabetes mellitus, and hepatic, pulmonary, and renal dysfunction.

Cone-rod dystrophy. In most affected individuals, visual problems present as progressive cone dystrophy resulting in visual impairment, photophobia, and nystagmus between birth and age 15 months. Full-field electroretinography (ERG), required to establish the diagnosis of cone-rod dystrophy, is abnormal from birth, eventually with impairment of both cone and rod function. Rod function is preserved initially but deteriorates as the individual ages, with visual acuity of 6/60 or less by age ten years, increasing constriction of visual fields, and no light perception by age 20 years. In some rare cases, some vision (e.g., the ability to read large print) is retained into the third decade. The severity and age of onset of the retinal degeneration vary among affected individuals [Malm et al 2008].

Fundus examination in the first decade may be normal or may show a pale optic disc and narrowing of the retinal vessels. Posterior subcapsular cataracts are common, even in the absence of diabetes.

Obesity. Children with Alström syndrome have normal birth weight. Hyperphagia and excessive weight gain (some studies show weight gain greater than expected for intake) begin during their first year, resulting in childhood truncal obesity. In some individuals body weight tends to normalize, decreasing into the high-normal to normal range after adolescence. The degree of obesity may mirror cultural background, with higher levels in North America than in South America, Turkey, Japan, and parts of Europe [Koç et al 2006].

Progressive bilateral sensorineural hearing loss. Hearing loss may be detected as early as age one year, initially in the high frequency range. Progressive sensorineural hearing loss presents in the first decade in as many as 70% of individuals with Alström syndrome. Hearing loss may progress to the severe or moderately severe range (40-70 db) by the end of the first to second decade [Van den Abeele et al 2001]. A high incidence of glue ear (long-standing sticky fluid in the middle ear) can lead to an additional conductive hearing loss [Marshall et al 2005].

Cardiomyopathy. More than 60% of individuals with Alström syndrome develop congestive heart failure as a result of cardiomyopathy at some stage of their lives. Onset, progression, and clinical outcome of the cardiomyopathy vary, even within families [Makaryus et al 2003, Hoffman et al 2005].

More than 40% of affected infants have a transient but severe dilated cardiomyopathy with onset between age three weeks and four months [Marshall et al 2005]. Most of these children survive and make an apparently full recovery in infancy. At a later age about 10%-15% of this group have spontaneous recurrence of a progressive restrictive cardiomyopathy. The proportion of those with Alström syndrome who develop infantile-onset cardiomyopathy may be underestimated because some infants who succumb may have undiagnosed Alström syndrome.

About 20% of individuals with Alström syndrome have later-onset progressive restrictive cardiomyopathy identified between the teens to late 30s. Postmortem myocardial fibrosis has been described [Marshall et al 2005]. Cardiac magnetic resonance imaging suggests that myocardial fibrosis may be present in clinically affected and asymptomatic individuals [Loudon et al 2009].

Insulin resistance/type 2 diabetes mellitus. Diabetes mellitus in Alström syndrome is the result of tissue resistance to the actions of insulin, as demonstrated by an elevated plasma insulin concentration and glucose intolerance that usually present in childhood. The age at which type 2 diabetes mellitus develops varies; it may be as early as age five years. Type 2 diabetes mellitus and insulin resistance are typically accompanied by the skin changes of acanthosis nigricans, i.e., velvety hyperpigmented patches in intertriginous areas.

In a small study of 12 unrelated individuals with Alström syndrome, obesity (BMI and waist circumference) decreased with age, whereas insulin resistance increased with age [Minton et al 2006].

Coronary artery disease as a result of insulin resistance, diabetes, dyslipidemia, and renal failure has been reported in one affected individual [Jatti et al 2012]. Diabetic peripheral neuropathy with risk of foot ulceration (which would be expected to develop) has been found to occur rarely if at all [Paisey et al 2009].

Hyperlipidemia. Hyperlipidemia is primarily hypertriglyceridemia, but can sometimes include high serum concentration of total cholesterol. Affected individuals are at risk for sudden increase in triglycerides precipitating life-threatening pancreatitis [Wu et al 2003].

Developmental delay. About 20% of affected individuals have delay in early developmental milestones including delays in gross and fine motor skills and in expressive and receptive language. About 30% have a learning disability. Cognitive impairment (IQ <70) is very rare.

Short stature. Growth rates for young children are normal, but accelerated skeletal maturity (2-3 years advanced bone age) and low-serum growth hormone concentrations result in adult stature that is typically less than the 25th centile. In about 98% of individuals over age 16 years height is below the fifth centile [Maffei et al 2007].

Scoliosis or kyphosis, beginning in puberty, is common [Maffei et al 2002].

Male pubertal development. There is a variable mixture of hypogonadotropic hypogonadism and testicular fibrosis which can result in delayed or arrested puberty. As a result secondary sexual characteristics may be normal or immature; gynecomastia may be present [Marshall et al 2005]. This mixed causality has meant that puberty is induced and androgenization maintained with testosterone rather than gonadotropins. Male fertility has not been systematically studied in the syndrome but has not been reported in an affected individual with pathogenic variants in both copies of ALMS1.

Female pubertal development. Endocrine disturbances in females include reduced plasma gonadotropin concentrations, hirsutism, polycystic ovarian syndrome consistent with insulin resistance, precocious puberty (pubertal onset before age 8 years), endometriosis, irregular menses, or amenorrhea. External genitalia are normal in females, though breast development is often poor. Fertility in females has not been systematically studied. Although a molecular diagnosis was not confirmed, one clinical report describes two unrelated females with late presentation of the syndrome, each of whom had healthy children [Iannello et al 2004].

Urologic disease. Urinary problems affect approximately 50% of individuals with Alström syndrome. Urologic disorders of varying severity, characterized by detrusor-urethral dyssynergia (lack of coordination of bladder and urethral muscle activity), have been described. The greatest problems appear to occur in females in their late teens. Minor symptoms include urgency and long intervals between voiding, which suggests a decrease in bladder sensation, hesitancy, and poor urinary flow. Moderate symptoms include urinary frequency, incontinence, and symptoms associated with recurrent infections. More severe urinary symptoms include worsening urinary incontinence or retention; these symptoms may alternate. Lower abdominal and perineal pain is common and may relate to abnormal bladder/sphincter function [MacDermott 2001]. Intermittent self-catheterization has been helpful in a small number of affected individuals and cystectomy with an ileal conduit has been performed in isolated severe cases.

Renal disease is common, slowly progressive, and highly variable, and may be unrelated to diabetes; it manifests as tubulo-interstitial disease resulting from interstitial fibrosis. Initial signs of mildly elevated serum concentrations of creatinine and blood urea nitrogen (BUN) may be followed by polyuria and polydipsia resulting from a concentrating defect. Onset can be in mid-childhood through adulthood. End-stage renal disease (ESRD) can occur as early as the mid- to late teens.

Renal biopsy often shows interstitial fibrosis, glomerular hyalinosis, and tubular atrophy [Marshall et al 2005].

Obstructive uropathy is rare.

Hepatic disease. Elevated plasma concentration of liver enzymes is common in early childhood. Macrovesicular steatosis and hepatomegaly can be present or absent. Progression to cirrhosis and hepatic failure can occur in the second to third decades, and the complications of portal hypertension, ascites, splenomegaly, hepatic encephalopathy, and esophageal varices are also seen.

Liver biopsies and postmortem examination have revealed varying degrees of steatohepatitis, hepatic fibrosis, cirrhosis, chronic nonspecific active hepatitis with lymphocytic infiltration, patchy necrosis, and fatty liver [Quiros-Tejeira et al 2001, Marshall et al 2005].

Gastrointestinal disease. General GI disturbances such as epigastric pain and gastroesophageal reflux disease (GERD) are common. Cecal volvulus without adhesions or obstructive lesions was reported in a sibling pair, raising the possibility of a generalized smooth muscle dysfunction in the syndrome [Khoo et al 2009].

Pulmonary involvement. Recurrent chest infections are common at all ages, but establishment of COPD is problematic because of difficulty in accurate performance of spirometry. Most frequently there is a combination of restrictive lung disease due to kyphoscoliosis and sometimes pulmonary fibrosis, which has been confirmed in post mortem tissue and may be detected in life with high-resolution chest CT scan. This may progress (with the added effects of cardiomyopathy) to pulmonary hypertension. The resulting susceptibility to severe hypoxia postoperatively or during episodes of pneumonia has been reported [Khoo et al 2009, Florentzson et al 2010].

Other

• Scoliosis and kyphosis of varying severity are reported in 30%-70% of individuals with Alström syndrome [Van den Abeele et al 2001, Marshall et al 2005].
• Severe flat feet and dental abnormalities have been observed [Koray et al 2001, Marshall et al 2005].
• Hypothyroidism has been reported in nearly 20% of individuals [Marshall et al 2005]; hyperthyroidism occurs infrequently [Ozgül et al 2007].
• Hypertension, often beginning in childhood, has been described in 30% of individuals [Marshall et al 2005].
• Neurobehavioral manifestations such as absence seizures, excessive startle response, severe and unexplained peripheral pain, and mild autistic spectrum behaviors have been reported [Marshall et al 2005].

Genotype-Phenotype Correlations

In one study involving fewer than 12 kindreds, no correlations were found between pathogenic variant position and the occurrence of specific clinical features, such as dilated cardiomyopathy [Minton et al 2006].

A separate genotype-phenotype association study of 58 affected individuals [Marshall et al 2007b] found suggestive associations between disease-causing variants in exon 16 of ALMS1 and the following findings:

• Onset of retinal degeneration before age one year (P=0.02)
  AND
• Occurrence of urologic dysfunction (P=0.02), diabetes mellitus (P=0.03), and dilated cardiomyopathy (P=0.03)

A more significant association was found between alterations in exon 8 and absent, mild, or delayed renal disease (P=0.0007).

This preliminary observation may have implications for the understanding of how alternative splicing of ALMS1 contributes to the severity of the disease, and thus provide useful information to clinicians.

Penetrance

No clinically unaffected individuals with two ALMS1 pathogenic variants in trans have been reported; thus, penetrance appears to be 100% [Marshall et al 2011a].

Prevalence

The prevalence of Alström syndrome is difficult to estimate; it is likely underdiagnosed because of its rarity. Estimates of the prevalence range from 1:10,000 [Minton et al 2006] to fewer than 1:1,000,000 [Marshall et al 2011b, Orphanet].

About 800 individuals diagnosed with Alström syndrome have been identified worldwide.

Ethnically or geographically isolated populations have a higher-than-average frequency of Alström syndrome [Deeble et al 2000, Ozgül et al 2007, Aldahmesh et al 2009].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Alström syndrome, a complete history of disease should direct detailed physical examination and investigations. A multidisciplinary team should be established to formulate and coordinate monitoring, management, and therapeutic interventions.

• Cone-rod dystrophy. Ophthalmologic evaluation, including electroretinogram and visual field testing
• Obesity. Measurement of weight and height; calculation of body mass index (BMI)
• Progressive sensorineural hearing loss. Audiometry with auditory brain stem response (ABR) and otoacoustic emissions (OAE) to detect sensorineural or conductive hearing loss; assessment of otitis media and conductive hearing loss
• Dilated cardiomyopathy. A detailed cardiac history and examination, including auscultation, echocardiography and ECGs. Echocardiography is required to demonstrate ventricular dilation, fibrosis, and decreased myocardial function.
• Insulin resistance/type 2 diabetes mellitus
  • Fasting plasma glucose, even in infancy
  • A glucose tolerance test (GTT) as early as age six years
  • Plasma insulin concentration, as hyperinsulinemia may be present from infancy
• Hyperlipidemia. A fasting lipid profile, including triglycerides
• Endocrine abnormalities
  • Assessment of thyroid function, including plasma TSH and free T4 concentration. If hyperthyroidism is suspected, free T3 concentration should be done.
  • Measurement of pituitary hormones
• Urologic
  • History to document urinary difficulties
  • If the individual is symptomatic or if urinalysis is abnormal, renal ultrasound examination to detect pelvi-calyceal dilatation and bladder ultrasound examination to measure post-voiding residual volumes
• Renal disease
  • Baseline blood pressure; 24-hour blood pressure monitoring
  • Measurement of plasma BUN, creatinine, urea and electrolytes. If renal function testing is abnormal, ultrasound examination. If abnormalities, refer to a nephrologist.
• Hepatic disease
  • Measurement of plasma ALT, AST, and GGT concentration
  • Liver ultrasonography to evaluate for possible hepatomegaly and portal hypertension
  • If clinically indicated, screening esophagogastroduodenoscopy for varices
• Pulmonary disease. Detailed assessment of pulmonary function by chest radiography, combined with pulmonary function tests
• Developmental assessment. Educational evaluation for intervention and IEP
• Other
  • Gastrointestinal. If symptoms of reflux esophagitis remain severe, despite acid blockers, perform barium swallow or upper gastrointestinal endoscopy.
  • Skin. Note acanthosis nigricans (indication of insulin resistance/diabetes mellitus), alopecia, body hair, hirsutism on physical examination.
  • Orthopedic abnormalities. Note flat feet, scoliosis, barrel chest, kyphoscoliosis on physical examination.
  • Neurologic manifestations. Neurologic evaluation with EEG to examine for seizures. Note autistic-spectrum behavioral abnormalities, excessive startle, tactile defensiveness, unexplained joint or muscle pain, muscle dystonia, or hyporeflexia.
  • Medical genetics consultation

Treatment of Manifestations

No therapy exists to prevent the progressive organ involvement. However, monitoring for developing problems and early intervention is essential.

Rod-cone dystrophy

• Early on when photodysphoria is significant, the use of red-orange tinted prescription lenses may reduce symptoms.
• Early educational planning should be based on the certainty of blindness. Instruction in the use of Braille, mobility training, adaptive living skills, and computing skills (including voice recognition and transcription software), and the use of large print reading materials while vision is still present are crucial.

Obesity. A healthful, reduced calorie diet and regular exercise, such as walking, hiking, biking, and swimming with adaptations for the blind, are recommended to control weight gain.

Progressive sensorineural hearing loss

• Myringotomy has been helpful in individuals with recurrent otitis media (‘glue ear’).
• Hearing can be maximized with bilateral digital hearing aids.
• Cochlear implantation has benefitted some patients [Florentzson et al 2010].

Cardiomyopathy. Angiotensinogen-converting enzyme (ACE) inhibitors, diuretics, digoxin, and possibly beta-blockers should be used in the treatment of cardiac failure. Cardiac transplantation has been successful in isolated cases [Goerler et al 2007].

Insulin resistance/type 2 diabetes should be treated as in the general population unless heart failure and/or liver dysfunction are present. The diabetes mellitus is characterized by insulin resistance, but some individuals respond to a low-sugar, low-fat diet; exercise; and metformin. Glitazones are added to further reduce insulin resistance but must be avoided in the presence of active or treated heart failure. These treatments should be discontinued when the serum creatinine concentration exceeds 200 µmol/L or if cardiomyopathy is evident. Incretin analogues given subcutaneously, as in nonsyndromic type 2 diabetes, are successful in two thirds of cases [Paisey et al 2008, Paisey 2009].

Hypertriglyceridemia

• Nicotinic acid derivatives can be helpful in long-term reduction of severe hypertriglyceridemia (>20 mmol/l) especially if pancreatitis has occurred and diabetes is absent or well controlled [Paisey et al 2004, Paisey 2009]. Statins are unlikely to be effective but can be considered for long-term prevention of atherosclerosis in adults with low HDL, high LDL, and diabetes.
• Pancreatitis should be treated as in the general population.

Endocrine

• As children approach puberty, gonadotropin and pituitary hormones should be assessed to determine if hormonal adjustments are necessary.
• Male hypogonadism should be treated with testosterone according to local endocrine guidelines to preserve sexuality, muscle strength, and bone health.
• Thyroxine therapy should be initiated and monitored if the individual is hypothyroid.

Urologic. Some individuals have required urinary diversion or self-catheterization to manage voiding difficulties [MacDermott 2001].

Renal disease

• The use of enzyme ACE inhibitors may be considered if proteinuria is detected.
• Successful renal transplantation has occurred in a growing number of individuals, but can be contraindicated in the presence of other complications including morbid obesity, uncontrolled diabetes, and cardiomyopathy.

Hepatic disease. Portal hypertension may be treated with beta-blockade and sclerotherapy of the esophageal veins. Banding should be done in order to prevent upper-GI hemorrhage from varices. Patients who fail to respond to medication and banding are candidates for a transjugular intrahepatic portosystemic shunt (TIPS) to decrease risk of variceal bleeding caused by portal hypertension. Patients with significant portal hypertension should be evaluated early for liver transplantation.

Pulmonary disease. General activity, including breathing exercises, can reduce chronic hypoxia and improve wellbeing. Coaching by an exercise expert may be necessary in order to achieve adequate spirometry results to determine the presence of obstructive airways disease.

Other

• If skeletal abnormalities are present, referral to an orthopedist is appropriate.
• Reflux esophagitis, skin manifestations, orthopedic abnormalities, and neurologic manifestations should be treated as in the general population.
• Education intervention, as indicated by evaluation and IEP (individual education plan) with the expectation of total blindness and hearing loss.

Prevention of Primary Complications

The progression to diabetes mellitus and the severity of hyperglycemia can in some cases be mitigated by lifestyle changes and avoidance of severe obesity.

Prevention of Secondary Complications

Routine pediatric immunizations should be given and administration of pneumococcal vaccination should be considered.

Care must be taken during sedation or operative procedures. The combination of dilated cardiomyopathy, congestive heart failure, pulmonary hypertension, and pulmonary fibrosis can cause sudden severe hypoxia in an affected individual following surgery or even during a minor infection. Close monitoring of cardiac status and oxygenation are necessary until the individual is fully recovered.

Surveillance

Rod-cone dystrophy. Annual ophthalmologic follow-up is indicated as long as the affected individual has vision.

Obesity. Weight, height, and body mass index (BMI) should be recorded annually and plotted on growth curves.

Progressive sensorineural hearing loss. Audiometry should be performed yearly.

Cardiomyopathy

• A detailed cardiac history and examination including echocardiography annually even in the absence of symptoms related to left ventricular dysfunction (signs of cardiac failure, such as sweating, fatigue, lethargy, asthma, decreased physical activity)
• ECGs in parallel with echocardiography and 24-hour ECG monitoring if indicated
• In individuals who have had infantile cardiomyopathy, annual monitoring by a pediatric cardiologist, even if the individual has recovered from cardiomyopathy and is asymptomatic

Insulin resistance/type 2 diabetes

• Annual measurement of plasma insulin concentration, as hyperinsulinemia may be present from early infancy
• Measurement of fasting plasma glucose concentration every two to three months
• If fasting blood glucose is greater than 7 mmol/L, or postprandial blood glucose is greater than 11 mmol/L, measurement of HbA1c concentration and serum glucose concentration regularly (every 6 months, although glucose estimations may be performed more frequently as determined by the 'diabetic control' of the affected individual)

Hyperlipidemia. Annual total lipid profile determination is appropriate unless hyperlipidemia is present, in which case more frequent monitoring may be indicated. When the affected individual is ill and/or dehydrated, pancreatitis precipitated by hyperlipidemia can be life threatening.

Renal disease

• Urinalysis and measurement of plasma concentrations of electrolytes, uric acid, BUN, and creatinine twice yearly
• Renal and bladder ultrasound examinations every one to two years if the individual is symptomatic or if urinalysis is abnormal

Hepatic disease

• Annual measurement of plasma ALT, AST, and GGT concentration
• Ultrasonography to evaluate for possible steatosis, hepatomegaly, cirrhosis, and portal hypertension

Pulmonary disease. Pulmonary function tests should be performed yearly to evaluate general lung function, even if symptoms of pulmonary fibrosis are not yet present.

Hypothyroidism. Patients should be monitored annually for thyroid abnormalities.

Agents/Circumstances to Avoid

Any substance contraindicated in persons with renal or cardiac failure should be avoided.

Therapy directed at one system may have adverse effects on other systems; for example, the use of glitazone therapy in diabetes mellitus is contraindicated in the presence of cardiac failure.

Evaluation of Relatives at Risk

Early evaluation and/or molecular genetic testing (if the two pathogenic allelic variants in a family are known) of at-risk sibs allows for early diagnosis and early treatment of manifestations.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

There are no data to guide the management of a pregnancy should it occur in a female with Alström syndrome. Potential maternal complications during pregnancy could include development or worsening of cardiac, renal, or hepatic failure; severe dyslipidemia; and hyperglycemia. The fetus could be affected by placental dysfunction resulting from maternal diabetes and cardiorenal disease. Intensive multidisciplinary surveillance of any pregnancy would be mandatory.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Alström syndrome is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes and therefore carry one mutated allele.
• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.

Offspring of a proband. No individuals with molecularly confirmed Alström syndrome are known to be fertile.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the pathogenic variants have been identified in a family member.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the ALMS1 pathogenic variants have been identified in the family, prenatal diagnosis or preimplantation genetic diagnosis for a pregnancy at increased risk for Alström syndrome may be an option that a couple may wish to consider.

Literature Cited

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Author History

Catherine Carey, MD, FRCP (2003-present)
Ian Hopkinson, BSc (Hons), MBChB, PhD, MRCGP; University College London (2003-2010)
Seamus Macdermott, MD, FRCS (2003-present)
Jan D Marshall, MS (2003-present)
Richard B Paisey, MD, FRCP (2005-present)

Revision History

• 31 May 2012 (me) Comprehensive update posted live
• 8 June 2010 (me) Comprehensive update posted live
• 25 June 2007 (me) Comprehensive update posted to live Web site
• 7 February 2005 (me) Comprehensive update posted to live Web site
• 11 May 2004 (ih) Revision: test availability
• 7 February 2003 (me) Review posted to live Web site
• 6 June 2002 (ih) Original submission