2-year-old Singapore boy is one of estimated 400 in world with disease caused by single altered gene

SINGAPORE - During Tizane Woo's 20-week prenatal scan, her doctor noticed something was not right with her child, Teyden Hamilton Ho.

"They told us that his head was smaller than average. The circumference of his hindbrain (cerebellum) was too small," said the 26-year-old housewife.

"A week after I went for amniocentesis in the 22nd week of my pregnancy, I was told that Teyden has an additional chromosome, which was inherited from me."

She and her husband were asked if they wanted to abort the child because of all the issues he could face.

"But not once did we think of doing so because he was ours," Woo said.

When Teyden was 15 months old, he was diagnosed with Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome after blood samples from all three of them were sent to the US for testing.

The condition, named after the four doctors and researchers who identified it in 2016, is a rare hereditary disease caused by a single altered gene on a non-sex chromosome.

Broadly speaking, it affects brain development.

There is no figure available for how many people in the world have the condition, as it was only recently recognised, said geneticist Jeannette Goh, a consultant in the Department of Genomic Medicine at KK Women's and Children's Hospital (KKH).

She said it is believed that there are about 400 people who have the disease.

Woo's obstetrician and gynaecologist Tony Tan had referred her to Goh.

"The symptoms of ZTTK syndrome are related to what the SON gene does. The gene acts like an editor for other genes and helps the body read other gene instructions, and many of these other genes are related to brain development," said Goh.

"When the instructions get disrupted, we do get issues in intellectual and cognitive functions. Together with that, we see many developmental delays, such as in their motor skills, breathing and speech. That is why we put (patients) into learning intervention programmes early."

Goh said the possibility of the condition being missed, misdiagnosed or even undiagnosed is high because ZTTK syndrome is very rare and its symptoms overlap with other neurological conditions.

Genetic counsellor Priscella Chia from KKH, who also attends to Teyden, said it is "entirely normal for the first few tests to come back inconclusive".

"About 80 per cent of rare diseases present with vague, overlapping symptoms. Standard medical tests (like basic blood work or imaging) usually rule out common conditions rather than pinpoint a rare one," she added.

Woo said it was an emotional roller coaster for her and her husband when Teyden was diagnosed.

"I felt sad that I was the one who gave him his condition. At the same time, we were happy that we finally had a diagnosis for Teyden's condition. We also had a lot of help from his physiotherapists, who have taught us how to manage him," she said.

"It helps also that Teyden is a super happy child, and it makes it easy for us to take care of him."

Teyden now attends physiotherapy twice a week to work on his posture, trunk control and overall motor function at the Wings Therapy and Learning Centre in Singapore.

"We started intensive sessions in June, and it helped him a lot. Now he is able to sit up on his own for a period of time, which he could not do before. He was really floppy, and his head control was very weak," Woo said.

Teyden also tends to shake his arms and move his head to hit the back of his high chair, a known neurological manifestation of ZTTK syndrome associated with several central nervous system anomalies.

"He cries when we stop him. To prevent him from hurting himself, we have put a cushion behind him. (But) he seems to know it is soft, so he goes at it harder. He is cheeky that way," Woo said.

At the end of May, Teyden started having seizures, a symptom that affects between 50 per cent and 55 per cent of ZTTK syndrome patients.

"We did not know they were seizures. He was still on the BiPAP. He was still asleep, jerking. There was foam coming from his mouth, and he was slowly turning blue. We called the ambulance," Woo said.

A BiPAP machine is a non-invasive ventilator used to help with breathing by delivering pressurised air through a mask: Higher pressure for inhalation and lower pressure for exhalation.

When Teyden had another seizure weeks later, his parents were ready with the video camera, and they managed to capture the 11-minute incident and report it to the attending doctor at the emergency room in KKH.

Teyden is on anti-seizure medication, but he still experienced another episode - this time brought on by fever and Covid-19. This meant he could have faced a significantly higher risk of severe symptoms or respiratory complications.

"It was the scariest point of the two years of his life," his mother said.

Having recovered, Teyden is back to playing with the two family pets and attending classes at Fei Yue EIPIC Centre in Upper Thomson Road, which offers an early intervention programme for young children with developmental and special needs.

"He is the youngest there, and the loudest in class," Woo said, laughing.

Teyden's father Ho Jun Han, 27, a data centre operator, said the boy likes to be involved in conversations and babbles a lot, even though he cannot form words.

They have joined a Facebook support group that is based in the US.

"Apart from Teyden, there is no one else in Singapore with his condition. It was here on this Facebook page that we got to see other kids with ZTTK, contact parents dealing with the condition and perhaps provide support for each other," Woo said.

"We do not know what the future holds for him because this condition is super rare... We are managing and trying to stay as positive as much as possible."

This article was first published in The Straits Times . Permission required for reproduction.

新加坡——在蒂赞·伍 (Tizane Woo) 怀孕 20 周进行产前扫描时，她的医生发现她的孩子泰登·汉密尔顿·何 (Teyden Hamilton Ho) 有些不对劲。

“他们告诉我们，他的头比平均水平小。他的后脑（小脑）周长也太小了，”这位26岁的家庭主妇说道。

“在我怀孕第 22 周进行羊膜穿刺一周后，我被告知泰登多了一条染色体，这条染色体是从我这里遗传的。”

有人问她和她丈夫是否想堕胎，因为孩子可能会面临很多问题。

“但我们从未想过要这样做，因为他是我们的，”伍说。

泰登 15 个月大的时候，他被诊断出患有朱-时田-竹之内-金（ZTTK）综合征，此前他们三人的血液样本被送到美国进行检测。

这种疾病以 2016 年发现它的四位医生和研究人员的名字命名，是一种罕见的遗传性疾病，由非性染色体上的单个基因改变引起。

总的来说，它会影响大脑发育。

遗传学家、KK妇女儿童医院（KKH）基因组医学部顾问Jeannette Goh表示，由于这种疾病是最近才被发现的，因此目前还没有关于全世界有多少人患有这种疾病的统计数据。

她说，据信约有400人患有这种疾病。

Woo 的妇产科医生 Tony Tan 将她转诊给了 Goh。

“ZTTK综合征的症状与SON基因的功能有关。该基因就像其他基因的编辑器，帮助身体读取其他基因的指令，而这些基因中有很多都与大脑发育有关，”吴医生说。

“当指令被打乱时，就会出现智力和认知功能方面的问题。同时，我们还会看到许多发育迟缓，例如运动技能、呼吸和语言方面的发育迟缓。这就是为什么我们要尽早将（患者）纳入学习干预计划的原因。”

Goh表示，由于ZTTK综合征非常罕见，而且其症状与其他神经系统疾病重叠，因此该疾病被漏诊、误诊甚至漏诊的可能性很高。

来自 KKH 的遗传咨询师 Priscella Chia 也为 Teyden 提供咨询，她说“最初几次检测结果不确定是完全正常的”。

她补充说：“大约80%的罕见病症状模糊且相互重叠。标准的医学检查（如基本的血液检查或影像学检查）通常只能排除常见疾病，而无法准确诊断出罕见病。”

Woo表示，Teyden被确诊后，她和丈夫的情绪就像坐过山车一样。

“我很难过，因为是我让他患上了这种病。但同时，我们也为终于确诊泰登的病情而感到高兴。他的理疗师们也给了我们很多帮助，他们教会了我们如何照顾他，”她说。

“泰登是个非常快乐的孩子，这也有助于我们照顾他。”

Teyden 现在每周两次前往新加坡的 Wings 治疗和学习中心接受物理治疗，以改善他的姿势、躯干控制和整体运动功能。

“我们从六月份开始进行强化训练，这对他帮助很大。现在他可以自己坐起来一段时间了，这是他以前做不到的。他以前身体很软，头部控制能力也很差，”伍医生说。

泰登还经常摇晃手臂，并转动头部撞击高脚椅的椅背，这是 ZTTK 综合征的一种已知的神经系统表现，与几种中枢神经系统异常有关。

“我们阻止他的时候，他会哭。为了防止他受伤，我们在他身后放了一个垫子。（但是）他好像知道垫子很软，所以反而更用力地去抓。他就是这么调皮，”伍说道。

5 月底，泰登开始出现癫痫发作，这是 50% 到 55% 的 ZTTK 综合征患者都会出现的症状。

“我们当时并不知道那是癫痫发作。他还在用双水平呼吸机。他当时还在睡梦中，身体却在抽搐。他嘴里吐出泡沫，脸色也慢慢发青。我们赶紧叫了救护车，”伍医生说。

BiPAP 呼吸机是一种无创呼吸机，通过面罩输送加压空气来帮助呼吸：吸气时压力较高，呼气时压力较低。

几周后，泰登再次癫痫发作，他的父母早已准备好了摄像机，他们设法记录下了这 11 分钟的事件，并将其报告给了 KKH 急诊室的主治医生。

泰登正在服用抗癫痫药物，但他仍然再次发作——这次是由发烧和新冠肺炎引起的。这意味着他可能面临更高的严重症状或呼吸系统并发症风险。

“那是他两年生命中最可怕的时刻，”他的母亲说。

康复后，泰登又可以和家里的两只宠物玩耍了，并且还在汤申路上段的飞跃早期干预中心上课。该中心为有发育和特殊需要的幼儿提供早期干预计划。

“他是班里年纪最小的，也是声音最大的，”伍笑着说。

Teyden 的父亲 Ho Jun Han 今年 27 岁，是一名数据中心运营商。他说，儿子喜欢参与对话，经常咿呀学语，尽管他不会说话。

他们加入了一个位于美国的Facebook互助小组。

“除了泰登之外，新加坡没有其他患有他这种疾病的人。正是在这个Facebook页面上，我们才能看到其他患有ZTTK的孩子，联系到正在应对这种疾病的家长，并互相提供支持，”伍说道。

“我们不知道他的未来会怎样，因为这种情况非常罕见……我们正在尽力应对，并努力保持乐观。”

本文最初发表于《海峡时报》。转载需获得许可。